International Journal of Molecular Sciences

Editorial

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10 pages, 247 KiB

Open AccessEditorial

Special Issue on “The Tight Junction and Its Proteins: More than Just a Barrier”

by Susanne M. Krug and Michael Fromm

Int. J. Mol. Sci. 2020, 21(13), 4612; https://doi.org/10.3390/ijms21134612 - 29 Jun 2020

Cited by 18 | Viewed by 3482

Abstract

For a long time, the tight junction (TJ) was known to form and regulate the paracellular barrier between epithelia and endothelial cell sheets. Starting shortly after the discovery of the proteins forming the TJ—mainly, the two families of claudins and TAMPs—several other functions [...] Read more.

For a long time, the tight junction (TJ) was known to form and regulate the paracellular barrier between epithelia and endothelial cell sheets. Starting shortly after the discovery of the proteins forming the TJ—mainly, the two families of claudins and TAMPs—several other functions have been discovered, a striking one being the surprising finding that some claudins form paracellular channels for small ions and/or water. This Special Issue covers numerous dedicated topics including pathogens affecting the TJ barrier, TJ regulation via immune cells, the TJ as a therapeutic target, TJ and cell polarity, the function of and regulation by proteins of the tricellular TJ, the TJ as a regulator of cellular processes, organ- and tissue-specific functions, TJs as sensors and reactors to environmental conditions, and last, but not least, TJ proteins and cancer. It is not surprising that due to this diversity of topics and functions, the still-young field of TJ research is growing fast. This Editorial gives an introduction to all 43 papers of the Special Issue in a structured topical order. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

Research

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18 pages, 3693 KiB

Open AccessArticle

Claudin-12 Knockout Mice Demonstrate Reduced Proximal Tubule Calcium Permeability

by Allein Plain, Wanling Pan, Deborah O’Neill, Megan Ure, Megan R. Beggs, Maikel Farhan, Henrik Dimke, Emmanuelle Cordat and R. Todd Alexander

Int. J. Mol. Sci. 2020, 21(6), 2074; https://doi.org/10.3390/ijms21062074 - 18 Mar 2020

Cited by 37 | Viewed by 4435

Abstract

The renal proximal tubule (PT) is responsible for the reabsorption of approximately 65% of filtered calcium, primarily via a paracellular pathway. However, which protein(s) contribute this paracellular calcium pore is not known. The claudin family of tight junction proteins confers permeability properties to [...] Read more.

The renal proximal tubule (PT) is responsible for the reabsorption of approximately 65% of filtered calcium, primarily via a paracellular pathway. However, which protein(s) contribute this paracellular calcium pore is not known. The claudin family of tight junction proteins confers permeability properties to an epithelium. Claudin-12 is expressed in the kidney and when overexpressed in cell culture contributes paracellular calcium permeability (P_Ca). We therefore examined claudin-12 renal localization and its contribution to tubular paracellular calcium permeability. Claudin-12 null mice (KO) were generated by replacing the single coding exon with β-galactosidase from Escherichia coli. X-gal staining revealed that claudin-12 promoter activity colocalized with aquaporin-1, consistent with the expression in the PT. PTs were microperfused ex vivo and P_Ca was measured. P_Ca in PTs from KO mice was significantly reduced compared with WT mice. However, urinary calcium excretion was not different between genotypes, including those on different calcium containing diets. To assess downstream compensation, we examined renal mRNA expression. Claudin-14 expression, a blocker of P_Ca in the thick ascending limb (TAL), was reduced in the kidney of KO animals. Thus, claudin-12 is expressed in the PT, where it confers paracellular calcium permeability. In the absence of claudin-12, reduced claudin-14 expression in the TAL may compensate for reduced PT calcium reabsorption. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

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18 pages, 5391 KiB

Open AccessArticle

Drinking and Water Handling in the Medaka Intestine: A Possible Role of Claudin-15 in Paracellular Absorption?

by Christian K. Tipsmark, Andreas M. Nielsen, Maryline C. Bossus, Laura V. Ellis, Christina Baun, Thomas L. Andersen, Jes Dreier, Jonathan R. Brewer and Steffen S. Madsen

Int. J. Mol. Sci. 2020, 21(5), 1853; https://doi.org/10.3390/ijms21051853 - 8 Mar 2020

Cited by 4 | Viewed by 3771

Abstract

When euryhaline fish move between fresh water (FW) and seawater (SW), the intestine undergoes functional changes to handle imbibed SW. In Japanese medaka, the potential transcellular aquaporin-mediated conduits for water are paradoxically downregulated during SW acclimation, suggesting paracellular transport to be of principal [...] Read more.

When euryhaline fish move between fresh water (FW) and seawater (SW), the intestine undergoes functional changes to handle imbibed SW. In Japanese medaka, the potential transcellular aquaporin-mediated conduits for water are paradoxically downregulated during SW acclimation, suggesting paracellular transport to be of principal importance in hyperosmotic conditions. In mammals, intestinal claudin-15 (CLDN15) forms paracellular channels for small cations and water, which may participate in water transport. Since two cldn15 paralogs, cldn15a and cldn15b, have previously been identified in medaka, we examined the salinity effects on their mRNA expression and immunolocalization in the intestine. In addition, we analyzed the drinking rate and intestinal water handling by adding non-absorbable radiotracers, 51-Cr-EDTA or 99-Tc-DTPA, to the water. The drinking rate was >2-fold higher in SW than FW-acclimated fish, and radiotracer experiments showed anterior accumulation in FW and posterior buildup in SW intestines. Salinity had no effect on expression of cldn15a, while cldn15b was approximately 100-fold higher in FW than SW. Despite differences in transcript dynamics, Cldn15a and Cldn15b proteins were both similarly localized in the apical tight junctions of enterocytes, co-localizing with occludin and with no apparent difference in localization and abundance between FW and SW. The stability of the Cldn15 protein suggests a physiological role in water transport in the medaka intestine. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

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20 pages, 6572 KiB

Open AccessArticle

Enteropathogenic Escherichia coli (EPEC) Recruitment of PAR Polarity Protein Atypical PKCζ to Pedestals and Cell–Cell Contacts Precedes Disruption of Tight Junctions in Intestinal Epithelial Cells

by Rocio Tapia, Sarah E. Kralicek and Gail A. Hecht

Int. J. Mol. Sci. 2020, 21(2), 527; https://doi.org/10.3390/ijms21020527 - 14 Jan 2020

Cited by 11 | Viewed by 4584

Abstract

Enteropathogenic Escherichia coli (EPEC) uses a type three secretion system to inject effector proteins into host intestinal epithelial cells, causing diarrhea. EPEC induces the formation of pedestals underlying attached bacteria, disrupts tight junction (TJ) structure and function, and alters apico-basal polarity by redistributing [...] Read more.

Enteropathogenic Escherichia coli (EPEC) uses a type three secretion system to inject effector proteins into host intestinal epithelial cells, causing diarrhea. EPEC induces the formation of pedestals underlying attached bacteria, disrupts tight junction (TJ) structure and function, and alters apico-basal polarity by redistributing the polarity proteins Crb3 and Pals1, although the mechanisms are unknown. Here we investigate the temporal relationship of PAR polarity complex and TJ disruption following EPEC infection. EPEC recruits active aPKCζ, a PAR polarity protein, to actin within pedestals and at the plasma membrane prior to disrupting TJ. The EPEC effector EspF binds the endocytic protein sorting nexin 9 (SNX9). This interaction impacts actin pedestal organization, recruitment of active aPKCζ to actin at cell–cell borders, endocytosis of JAM-A S285 and occludin, and TJ barrier function. Collectively, data presented herein support the hypothesis that EPEC-induced perturbation of TJ is a downstream effect of disruption of the PAR complex and that EspF binding to SNX9 contributes to this phenotype. aPKCζ phosphorylates polarity and TJ proteins and participates in actin dynamics. Therefore, the early recruitment of aPKCζ to EPEC pedestals and increased interaction with actin at the membrane may destabilize polarity complexes ultimately resulting in perturbation of TJ. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

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19 pages, 4022 KiB

Open AccessArticle

Regional Differences in Tight Junction Protein Expression in the Blood–DRG Barrier and Their Alterations after Nerve Traumatic Injury in Rats

by Thomas J. Lux, Xiawei Hu, Adel Ben-Kraiem, Robert Blum, Jeremy Tsung-Chieh Chen and Heike L. Rittner

Int. J. Mol. Sci. 2020, 21(1), 270; https://doi.org/10.3390/ijms21010270 - 31 Dec 2019

Cited by 15 | Viewed by 4110

Abstract

The nervous system is shielded by special barriers. Nerve injury results in blood–nerve barrier breakdown with downregulation of certain tight junction proteins accompanying the painful neuropathic phenotype. The dorsal root ganglion (DRG) consists of a neuron-rich region (NRR, somata of somatosensory and nociceptive [...] Read more.

The nervous system is shielded by special barriers. Nerve injury results in blood–nerve barrier breakdown with downregulation of certain tight junction proteins accompanying the painful neuropathic phenotype. The dorsal root ganglion (DRG) consists of a neuron-rich region (NRR, somata of somatosensory and nociceptive neurons) and a fibre-rich region (FRR), and their putative epi-/perineurium (EPN). Here, we analysed blood–DRG barrier (BDB) properties in these physiologically distinct regions in Wistar rats after chronic constriction injury (CCI). Cldn5, Cldn12, and Tjp1 (rats) mRNA were downregulated 1 week after traumatic nerve injury. Claudin-1 immunoreactivity (IR) found in the EPN, claudin-19-IR in the FRR, and ZO-1-IR in FRR-EPN were unaltered after CCI. However, laser-assisted, vessel specific qPCR, and IR studies confirmed a significant loss of claudin-5 in the NRR. The NRR was three-times more permeable compared to the FRR for high and low molecular weight markers. NRR permeability was not further increased 1-week after CCI, but significantly more CD68⁺ macrophages had migrated into the NRR. In summary, NRR and FRR are different in naïve rats. Short-term traumatic nerve injury leaves the already highly permeable BDB in the NRR unaltered for small and large molecules. Claudin-5 is downregulated in the NRR. This could facilitate macrophage invasion, and thereby neuronal sensitisation and hyperalgesia. Targeting the stabilisation of claudin-5 in microvessels and the BDB barrier could be a future approach for neuropathic pain therapy. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

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15 pages, 3067 KiB

Open AccessArticle

Tricellulin Effect on Paracellular Water Transport

by Carlos Ayala-Torres, Susanne M. Krug, Jörg D. Schulzke, Rita Rosenthal and Michael Fromm

Int. J. Mol. Sci. 2019, 20(22), 5700; https://doi.org/10.3390/ijms20225700 - 14 Nov 2019

Cited by 17 | Viewed by 3961

Abstract

In epithelia, large amounts of water pass by transcellular and paracellular pathways, driven by the osmotic gradient built up by the movement of solutes. The transcellular pathway has been molecularly characterized by the discovery of aquaporin membrane channels. Unlike this, the existence of [...] Read more.

In epithelia, large amounts of water pass by transcellular and paracellular pathways, driven by the osmotic gradient built up by the movement of solutes. The transcellular pathway has been molecularly characterized by the discovery of aquaporin membrane channels. Unlike this, the existence of a paracellular pathway for water through the tight junctions (TJ) was discussed controversially for many years until two molecular components of paracellular water transport, claudin-2 and claudin-15, were identified. A main protein of the tricellular TJ (tTJ), tricellulin, was shown to be downregulated in ulcerative colitis leading to increased permeability to macromolecules. Whether or not tricellulin also regulates water transport is unknown yet. To this end, an epithelial cell line featuring properties of a tight epithelium, Madin-Darby canine kidney cells clone 7 (MDCK C7), was stably transfected with small hairpin RNA (shRNA) targeting tricellulin, a protein of the tTJ essential for the barrier against passage of solutes up to 10 kDa. Water flux was induced by osmotic gradients using mannitol or 4 and 40 kDa-dextran. Water flux in tricellulin knockdown (KD) cells was higher compared to that of vector controls, indicating a direct role of tricellulin in regulating water permeability in a tight epithelial cell line. We conclude that tricellulin increases water permeability at reduced expression. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

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12 pages, 1801 KiB

Open AccessArticle

Celiac Disease Monocytes Induce a Barrier Defect in Intestinal Epithelial Cells

by Deborah Delbue, Danielle Cardoso-Silva, Federica Branchi, Alice Itzlinger, Marilena Letizia, Britta Siegmund and Michael Schumann

Int. J. Mol. Sci. 2019, 20(22), 5597; https://doi.org/10.3390/ijms20225597 - 9 Nov 2019

Cited by 15 | Viewed by 3367

Abstract

Intestinal epithelial barrier function in celiac disease (CeD) patients is altered. However, the mechanism underlying this effect is not fully understood. The aim of the current study was to evaluate the role of monocytes in eliciting the epithelial barrier defect in CeD. For [...] Read more.

Intestinal epithelial barrier function in celiac disease (CeD) patients is altered. However, the mechanism underlying this effect is not fully understood. The aim of the current study was to evaluate the role of monocytes in eliciting the epithelial barrier defect in CeD. For this purpose, human monocytes were isolated from peripheral blood mononuclear cells (PBMCs) from active and inactive CeD patients and healthy controls. PBMCs were sorted for expression of CD14 and co-cultured with intestinal epithelial cells (IECs, Caco2BBe). Barrier function, as well as tight junctional alterations, were determined. Monocytes were characterized by profiling of cytokines and surface marker expression. Transepithelial resistance was found to be decreased only in IECs that had been exposed to celiac monocytes. In line with this, tight junctional alterations were found by confocal laser scanning microscopy and Western blotting of ZO-1, occludin, and claudin-5. Analysis of cytokine concentrations in monocyte supernatants revealed higher expression of interleukin-6 and MCP-1 in celiac monocytes. However, surface marker expression, as analyzed by FACS analysis after immunostaining, did not reveal significant alterations in celiac monocytes. In conclusion, CeD peripheral monocytes reveal an intrinsically elevated pro-inflammatory cytokine pattern that is associated with the potential of peripheral monocytes to affect barrier function by altering TJ composition. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

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16 pages, 4953 KiB

Open AccessArticle

Tilivalline- and Tilimycin-Independent Effects of Klebsiella oxytoca on Tight Junction-Mediated Intestinal Barrier Impairment

by Nina A. Hering, Anja Fromm, Roland Bücker, Gregor Gorkiewicz, Ellen Zechner, Christoph Högenauer, Michael Fromm, Jörg-Dieter Schulzke and Hanno Troeger

Int. J. Mol. Sci. 2019, 20(22), 5595; https://doi.org/10.3390/ijms20225595 - 8 Nov 2019

Cited by 20 | Viewed by 4081

Abstract

Klebsiella oxytoca causes antibiotic-associated hemorrhagic colitis and diarrhea. This was attributed largely to its secreted cytotoxins tilivalline and tilimycin, inductors of epithelial apoptosis. To study whether Klebsiella oxytoca exerts further barrier effects, T84 monolayers were challenged with bacterial supernatants derived from tilivalline/tilimycin-producing AHC6 [...] Read more.

Klebsiella oxytoca causes antibiotic-associated hemorrhagic colitis and diarrhea. This was attributed largely to its secreted cytotoxins tilivalline and tilimycin, inductors of epithelial apoptosis. To study whether Klebsiella oxytoca exerts further barrier effects, T84 monolayers were challenged with bacterial supernatants derived from tilivalline/tilimycin-producing AHC6 or its isogeneic tilivalline/tilimycin-deficient strain Mut-89. Both preparations decreased transepithelial resistance, enhanced fluorescein and FITC-dextran-4kDa permeabilities, and reduced expression of barrier-forming tight junction proteins claudin-5 and -8. Laser scanning microscopy indicated redistribution of both claudins off the tight junction region in T84 monolayers as well as in colon crypts of mice infected with AHC6 or Mut-89, indicating that these effects are tilivalline/tilimycin-independent. Furthermore, claudin-1 was affected, but only in a tilivalline/tilimycin-dependent manner. In conclusion, Klebsiella oxytoca induced intestinal barrier impairment by two mechanisms: the tilivalline/tilimycin-dependent one, acting by increasing cellular apoptosis and a tilivalline/tilimycin-independent one, acting by weakening the paracellular pathway through the tight junction proteins claudin-5 and -8. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

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17 pages, 12683 KiB

Open AccessArticle

Temporal Effects of Quercetin on Tight Junction Barrier Properties and Claudin Expression and Localization in MDCK II Cells

by Enrique Gamero-Estevez, Sero Andonian, Bertrand Jean-Claude, Indra Gupta and Aimee K. Ryan

Int. J. Mol. Sci. 2019, 20(19), 4889; https://doi.org/10.3390/ijms20194889 - 2 Oct 2019

Cited by 14 | Viewed by 4059

Abstract

Kidney stones affect 10% of the population. Yet, there is relatively little known about how they form or how to prevent and treat them. The claudin family of tight junction proteins has been linked to the formation of kidney stones. The flavonoid quercetin [...] Read more.

Kidney stones affect 10% of the population. Yet, there is relatively little known about how they form or how to prevent and treat them. The claudin family of tight junction proteins has been linked to the formation of kidney stones. The flavonoid quercetin has been shown to prevent kidney stone formation and to modify claudin expression in different models. Here we investigate the effect of quercetin on claudin expression and localization in MDCK II cells, a cation-selective cell line, derived from the proximal tubule. For this study, we focused our analyses on claudin family members that confer different tight junction properties: barrier-sealing (Cldn1, -3, and -7), cation-selective (Cldn2) or anion-selective (Cldn4). Our data revealed that quercetin’s effects on the expression and localization of different claudins over time corresponded with changes in transepithelial resistance, which was measured continuously throughout the treatment. In addition, these effects appear to be independent of PI3K/AKT signaling, one of the pathways that is known to act downstream of quercetin. In conclusion, our data suggest that quercetin’s effects on claudins result in a tighter epithelial barrier, which may reduce the reabsorption of sodium, calcium and water, thereby preventing the formation of a kidney stone. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

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15 pages, 3080 KiB

Open AccessArticle

Apoptotic Fragmentation of Tricellulin

by Susanne Janke, Sonnhild Mittag, Juliane Reiche and Otmar Huber

Int. J. Mol. Sci. 2019, 20(19), 4882; https://doi.org/10.3390/ijms20194882 - 1 Oct 2019

Cited by 6 | Viewed by 3819

Abstract

Apoptotic extrusion of cells from epithelial cell layers is of central importance for epithelial homeostasis. As a prerequisite cell–cell contacts between apoptotic cells and their neighbors have to be dissociated. Tricellular tight junctions (tTJs) represent specialized structures that seal polarized epithelial cells at [...] Read more.

Apoptotic extrusion of cells from epithelial cell layers is of central importance for epithelial homeostasis. As a prerequisite cell–cell contacts between apoptotic cells and their neighbors have to be dissociated. Tricellular tight junctions (tTJs) represent specialized structures that seal polarized epithelial cells at sites where three cells meet and are characterized by the specific expression of tricellulin and angulins. Here, we specifically addressed the fate of tricellulin in apoptotic cells. Methods: Apoptosis was induced by staurosporine or camptothecin in MDCKII and RT-112 cells. The fate of tricellulin was analyzed by Western blotting and immunofluorescence microscopy. Caspase activity was inhibited by Z-VAD-FMK or Z-DEVD-FMK. Results: Induction of apoptosis induces the degradation of tricellulin with time. Aspartate residues 487 and 441 were identified as caspase cleavage-sites in the C-terminal coiled-coil domain of human tricellulin. Fragmentation of tricellulin was inhibited in the presence of caspase inhibitors or when Asp487 or Asp441 were mutated to asparagine. Deletion of the tricellulin C-terminal amino acids prevented binding to lipolysis-stimulated lipoprotein receptor (LSR)/angulin-1 and thus should impair specific localization of tricellulin to tTJs. Conclusions: Tricellulin is a substrate of caspases and its cleavage in consequence contributes to the dissolution of tTJs during apoptosis. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

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19 pages, 4223 KiB

Open AccessArticle

Curcumin Mitigates Immune-Induced Epithelial Barrier Dysfunction by Campylobacter jejuni

by Fábia Daniela Lobo de Sá, Eduard Butkevych, Praveen Kumar Nattramilarasu, Anja Fromm, Soraya Mousavi, Verena Moos, Julia C. Golz, Kerstin Stingl, Sophie Kittler, Diana Seinige, Corinna Kehrenberg, Markus M. Heimesaat, Stefan Bereswill, Jörg-Dieter Schulzke and Roland Bücker

Int. J. Mol. Sci. 2019, 20(19), 4830; https://doi.org/10.3390/ijms20194830 - 28 Sep 2019

Cited by 38 | Viewed by 4775

Abstract

Campylobacter jejuni (C. jejuni) is the most common cause of foodborne gastroenteritis worldwide. The bacteria induce diarrhea and inflammation by invading the intestinal epithelium. Curcumin is a natural polyphenol from turmeric rhizome of Curcuma longa, a medical plant, and is [...] Read more.

Campylobacter jejuni (C. jejuni) is the most common cause of foodborne gastroenteritis worldwide. The bacteria induce diarrhea and inflammation by invading the intestinal epithelium. Curcumin is a natural polyphenol from turmeric rhizome of Curcuma longa, a medical plant, and is commonly used in curry powder. The aim of this study was the investigation of the protective effects of curcumin against immune-induced epithelial barrier dysfunction in C. jejuni infection. The indirect C. jejuni-induced barrier defects and its protection by curcumin were analyzed in co-cultures with HT-29/B6-GR/MR epithelial cells together with differentiated THP-1 immune cells. Electrophysiological measurements revealed a reduction in transepithelial electrical resistance (TER) in infected co-cultures. An increase in fluorescein (332 Da) permeability in co-cultures as well as in the germ-free IL-10^−/− mouse model after C. jejuni infection was shown. Curcumin treatment attenuated the C. jejuni-induced increase in fluorescein permeability in both models. Moreover, apoptosis induction, tight junction redistribution, and an increased inflammatory response—represented by TNF-α, IL-1β, and IL-6 secretion—was observed in co-cultures after infection and reversed by curcumin. In conclusion, curcumin protects against indirect C. jejuni-triggered immune-induced barrier defects and might be a therapeutic and protective agent in patients. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

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20 pages, 1913 KiB

Open AccessArticle

Use of Modified Clostridium perfringens Enterotoxin Fragments for Claudin Targeting in Liver and Skin Cells

by Laura-Sophie Beier, Jan Rossa, Stephen Woodhouse, Sophia Bergmann, Holger B. Kramer, Jonas Protze, Miriam Eichner, Anna Piontek, Sabine Vidal-y-Sy, Johanna M. Brandner, Gerd Krause, Nicole Zitzmann and Jörg Piontek

Int. J. Mol. Sci. 2019, 20(19), 4774; https://doi.org/10.3390/ijms20194774 - 26 Sep 2019

Cited by 9 | Viewed by 4117

Abstract

Claudins regulate paracellular permeability in different tissues. The claudin-binding domain of Clostridium perfringens enterotoxin (cCPE) is a known modulator of a claudin subset. However, it does not efficiently bind to claudin-1 (Cldn1). Cldn1 is a pharmacological target since it is (i) an essential [...] Read more.

Claudins regulate paracellular permeability in different tissues. The claudin-binding domain of Clostridium perfringens enterotoxin (cCPE) is a known modulator of a claudin subset. However, it does not efficiently bind to claudin-1 (Cldn1). Cldn1 is a pharmacological target since it is (i) an essential co-receptor for hepatitis C virus (HCV) infections and (ii) a key element of the epidermal barrier limiting drug delivery. In this study, we investigated the potential of a Cldn1-binding cCPE mutant (i) to inhibit HCV entry into hepatocytes and (ii) to open the epidermal barrier. Inhibition of HCV infection by blocking of Cldn1 with cCPE variants was analyzed in the Huh7.5 hepatoma cell line. A model of reconstructed human epidermis was used to investigate modulation of the epidermal barrier by cCPE variants. In contrast to cCPEwt, the Cldn1-binding cCPE-S305P/S307R/S313H inhibited infection of Huh7.5 cells with HCV in a dose-dependent manner. In addition, TJ modulation by cCPE variant-mediated targeting of Cldn1 and Cldn4 opened the epidermal barrier in reconstructed human epidermis. cCPE variants are potent claudin modulators. They can be applied for mechanistic in vitro studies and might also be used as biologics for therapeutic claudin targeting including HCV treatment (host-targeting antivirals) and improvement of drug delivery. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

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12 pages, 2350 KiB

Open AccessArticle

Detailed Clinical Features of Deafness Caused by a Claudin-14 Variant

by Tomohiro Kitano, Shin-ichiro Kitajiri, Shin-ya Nishio and Shin-ichi Usami

Int. J. Mol. Sci. 2019, 20(18), 4579; https://doi.org/10.3390/ijms20184579 - 16 Sep 2019

Cited by 7 | Viewed by 3487

Abstract

Tight junctions are cellular junctions that play a major role in the epithelial barrier function. In the inner ear, claudins, occludin, tricellulin, and angulins form the bicellular or tricellular binding of membrane proteins. In these, one type of claudin gene, CLDN14, was [...] Read more.

Tight junctions are cellular junctions that play a major role in the epithelial barrier function. In the inner ear, claudins, occludin, tricellulin, and angulins form the bicellular or tricellular binding of membrane proteins. In these, one type of claudin gene, CLDN14, was reported to be responsible for human hereditary hearing loss, DFNB29. Until now, nine pathogenic variants have been reported, and most phenotypic features remain unclear. In the present study, genetic screening for 68 previously reported deafness causative genes was carried out to identify CLDN14 variants in a large series of Japanese hearing loss patients, and to clarify the prevalence and clinical characteristics of DFNB29 in the Japanese population. One patient had a homozygous novel variant (c.241C>T: p.Arg81Cys) (0.04%: 1/2549). The patient showed progressive bilateral hearing loss, with post-lingual onset. Pure-tone audiograms indicated a high-frequency hearing loss type, and the deterioration gradually spread to other frequencies. The patient showed normal vestibular function. Cochlear implantation improved the patient’s sound field threshold levels, but not speech discrimination scores. This report indicated that claudin-14 is essential for maintaining the inner ear environment and suggested the possible phenotypic expansion of DFNB29. This is the first report of a patient with a tight junction variant receiving a cochlear implantation. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

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19 pages, 7378 KiB

Open AccessArticle

Claudin-19 Is Regulated by Extracellular Osmolality in Rat Kidney Inner Medullary Collecting Duct Cells

by Annalisa Ziemens, Svenja R. Sonntag, Vera C. Wulfmeyer, Bayram Edemir, Markus Bleich and Nina Himmerkus

Int. J. Mol. Sci. 2019, 20(18), 4401; https://doi.org/10.3390/ijms20184401 - 7 Sep 2019

Cited by 6 | Viewed by 3506

Abstract

The inner medullary collecting duct (IMCD) is subject to severe changes in ambient osmolality and must either allow water transport or be able to seal the lumen against a very high osmotic pressure. We postulate that the tight junction protein claudin-19 is expressed [...] Read more.

The inner medullary collecting duct (IMCD) is subject to severe changes in ambient osmolality and must either allow water transport or be able to seal the lumen against a very high osmotic pressure. We postulate that the tight junction protein claudin-19 is expressed in IMCD and that it takes part in epithelial adaptation to changing osmolality at different functional states. Presence of claudin-19 in rat IMCD was investigated by Western blotting and immunofluorescence. Primary cell culture of rat IMCD cells on permeable filter supports was performed under different osmotic culture conditions and after stimulation by antidiuretic hormone (AVP). Electrogenic transepithelial transport properties were measured in Ussing chambers. IMCD cells cultivated at 300 mosm/kg showed high transepithelial resistance, a cation selective paracellular pathway and claudin-19 was mainly located in the tight junction. Treatment by AVP increased cation selectivity but did not alter transepithelial resistance or claudin-19 subcellular localization. In contrast, IMCD cells cultivated at 900 mosm/kg had low transepithelial resistance, anion selectivity, and claudin-19 was relocated from the tight junctions to intracellular vesicles. The data shows osmolality-dependent transformation of IMCD epithelium from tight and sodium-transporting to leaky, with claudin-19 expression in the tight junction associated to tightness and cation selectivity under low osmolality. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

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11 pages, 1078 KiB

Open AccessArticle

Antagonistic Effects of IL-4 on IL-17A-Mediated Enhancement of Epidermal Tight Junction Function

by Matthew G. Brewer, Takeshi Yoshida, Fiona I. Kuo, Sade Fridy, Lisa A. Beck and Anna De Benedetto

Int. J. Mol. Sci. 2019, 20(17), 4070; https://doi.org/10.3390/ijms20174070 - 21 Aug 2019

Cited by 25 | Viewed by 4030

Abstract

Atopic dermatitis (AD) is the most common chronic and relapsing inflammatory skin disease. AD is typically characterized by skewed T helper (Th) 2 inflammation, yet other inflammatory profiles (Th1, Th17, Th22) have been observed in human patients. How cytokines from these different Th [...] Read more.

Atopic dermatitis (AD) is the most common chronic and relapsing inflammatory skin disease. AD is typically characterized by skewed T helper (Th) 2 inflammation, yet other inflammatory profiles (Th1, Th17, Th22) have been observed in human patients. How cytokines from these different Th subsets impact barrier function in this disease is not well understood. As such, we investigated the impact of the canonical Th17 cytokine, IL-17A, on barrier function and protein composition in primary human keratinocytes and human skin explants. These studies demonstrated that IL-17A enhanced tight junction formation and function in both systems, with a dependence on STAT3 signaling. Importantly, the Th2 cytokine, IL-4 inhibited the barrier-enhancing effect of IL-17A treatment. These observations propose that IL-17A helps to restore skin barrier function, but this action is antagonized by Th2 cytokines. This suggests that restoration of IL-17/IL-4 ratio in the skin of AD patients may improve barrier function and in so doing improve disease severity. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

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12 pages, 2924 KiB

Open AccessArticle

Phosphatidylcholine Passes by Paracellular Transport to the Apical Side of the Polarized Biliary Tumor Cell Line Mz-ChA-1

by Wolfgang Stremmel, Simone Staffer and Ralf Weiskirchen

Int. J. Mol. Sci. 2019, 20(16), 4034; https://doi.org/10.3390/ijms20164034 - 19 Aug 2019

Cited by 10 | Viewed by 5638

Abstract

Phosphatidylcholine (PC) translocation into mucus of the intestine was shown to occur via a paracellular transport across the apical/lateral tight junction (TJ) barrier. In case this could also be operative in biliary epithelial cells, this may have implication for the pathogenesis of primary [...] Read more.

Phosphatidylcholine (PC) translocation into mucus of the intestine was shown to occur via a paracellular transport across the apical/lateral tight junction (TJ) barrier. In case this could also be operative in biliary epithelial cells, this may have implication for the pathogenesis of primary sclerosing cholangitis (PSC). We here evaluated the transport of PC across polarized cholangiocytes. Therefore, the biliary tumor cell line Mz-ChA-1 was grown to confluency. In transwell culture systems the translocation of PC to the apical compartment was analyzed. After 21 days in culture, polarized Mz-ChA-1 cells revealed a predominant apical translocation of choline containing phospholipids including PC with minimal intracellular accumulation. Transport was suppressed by TJ destruction employing chemical inhibitors and pretreatment with siRNA to TJ forming proteins as well as the apical transmembrane mucin 3 as PC acceptor. Apical translocation was dependent on a negative apical electrical potential created by the cystic fibrosis transmembrane conductance regulator (CFTR) and the anion exchange protein 2 (AE2). It was stimulated by apical application of secretory mucins. The results indicated the existence of a paracellular PC passage across apical/lateral TJ of the polarized biliary epithelial tumor cell line Mz-ChA-1. This has implication for the generation of a protective mucus barrier in the biliary tree. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

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16 pages, 3045 KiB

Open AccessArticle

Brazilian Green Propolis Rescues Oxidative Stress-Induced Mislocalization of Claudin-1 in Human Keratinocyte-Derived HaCaT Cells

by Kana Marunaka, Mao Kobayashi, Shokoku Shu, Toshiyuki Matsunaga and Akira Ikari

Int. J. Mol. Sci. 2019, 20(16), 3869; https://doi.org/10.3390/ijms20163869 - 8 Aug 2019

Cited by 17 | Viewed by 4504

Abstract

Claudin-1 (CLDN1) is expressed in the tight junction (TJ) of the skin granular layer and acts as a physiological barrier for the paracellular transport of ions and nonionic molecules. Ultraviolet (UV) and oxidative stress may disrupt the TJ barrier, but the mechanism of [...] Read more.

Claudin-1 (CLDN1) is expressed in the tight junction (TJ) of the skin granular layer and acts as a physiological barrier for the paracellular transport of ions and nonionic molecules. Ultraviolet (UV) and oxidative stress may disrupt the TJ barrier, but the mechanism of and protective agents against this effect have not been clarified. We found that UVB and hydrogen peroxide (H₂O₂) caused the internalization of CLDN1 and increased the paracellular permeability of lucifer yellow, a fluorescent marker, in human keratinocyte-derived HaCaT cells. Therefore, the mechanism of mislocalization of CLDN1 and the protective effect of an ethanol extract of Brazilian green propolis (EBGP) were investigated. The UVB- and H₂O₂-induced decreases in CLDN1 localization were rescued by EBGP. H₂O₂ decreased the phosphorylation level of CLDN1, which was also rescued by EBGP. Wild-type CLDN1 was distributed in the cytosol after treatment with H₂O₂, whereas T191E, its H₂O₂-insensitive phosphorylation-mimicking mutant, was localized at the TJ. Both protein kinase C activator and protein phosphatase 2A inhibitor rescued the H₂O₂-induced decrease in CLDN1 localization. The tight junctional localization of CLDN1 and paracellular permeability showed a negative correlation. Our results indicate that UVB and H₂O₂ could induce the elevation of paracellular permeability mediated by the dephosphorylation and mislocalization of CLDN1 in HaCaT cells, which was rescued by EBGP. EBGP and its components may be useful in preventing the destruction of the TJ barrier through UV and oxidative stress. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

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13 pages, 2424 KiB

Open AccessArticle

Claudin-7 Modulates Cl⁻ and Na⁺ Homeostasis and WNK4 Expression in Renal Collecting Duct Cells

by Junming Fan, Rodney Tatum, John Hoggard and Yan-Hua Chen

Int. J. Mol. Sci. 2019, 20(15), 3798; https://doi.org/10.3390/ijms20153798 - 3 Aug 2019

Cited by 11 | Viewed by 3468

Abstract

Claudin-7 knockout (CLDN7^−/−) mice display renal salt wasting and dehydration phenotypes. To address the role of CLDN7 in kidneys, we established collecting duct (CD) cell lines from CLDN7^+/+ and CLDN7^−/− mouse kidneys. We found that deletion of CLDN7 increased [...] Read more.

Claudin-7 knockout (CLDN7^−/−) mice display renal salt wasting and dehydration phenotypes. To address the role of CLDN7 in kidneys, we established collecting duct (CD) cell lines from CLDN7^+/+ and CLDN7^−/− mouse kidneys. We found that deletion of CLDN7 increased the transepithelial resistance (TER) and decreased the paracellular permeability for Cl⁻ and Na⁺ in CLDN7^−/− CD cells. Inhibition of transcellular Cl⁻ and Na⁺ channels has no significant effect on TER or dilution potentials. Current-voltage curves were linear in both CLDN7^+/+ and CLDN7^−/− CD cells, indicating that the ion flux was through the paracellular pathway. The impairment of Cl⁻ and Na⁺ permeability phenotype can be rescued by CLDN7 re-expression. We also found that WNK4 (its mutations lead to hypertension) expression, but not WNK1, was significantly increased in CLDN7^−/− CD cell lines as well as in primary CLDN7^−/− CD cells, suggesting that the expression of WNK4 was modulated by CLDN7. In addition, deletion of CLDN7 upregulated the expression level of the apical epithelial sodium channel (ENaC), indicating a potential cross-talk between paracellular and transcellular transport systems. This study demonstrates that CLDN7 plays an important role in salt balance in renal CD cells and modulating WNK4 and ENaC expression levels that are vital in controlling salt-sensitive hypertension. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

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23 pages, 5751 KiB

Open AccessArticle

IL-13 Impairs Tight Junctions in Airway Epithelia

by Hanna Schmidt, Peter Braubach, Carolin Schilpp, Robin Lochbaum, Kathrin Neuland, Kristin Thompson, Danny Jonigk, Manfred Frick, Paul Dietl and Oliver H. Wittekindt

Int. J. Mol. Sci. 2019, 20(13), 3222; https://doi.org/10.3390/ijms20133222 - 30 Jun 2019

Cited by 37 | Viewed by 5537

Abstract

Interleukin-13 (IL-13) drives symptoms in asthma with high levels of T-helper type 2 cells (T_h2-cells). Since tight junctions (TJ) constitute the epithelial diffusion barrier, we investigated the effect of IL-13 on TJ in human tracheal epithelial cells. We observed that IL-13 [...] Read more.

Interleukin-13 (IL-13) drives symptoms in asthma with high levels of T-helper type 2 cells (T_h2-cells). Since tight junctions (TJ) constitute the epithelial diffusion barrier, we investigated the effect of IL-13 on TJ in human tracheal epithelial cells. We observed that IL-13 increases paracellular permeability, changes claudin expression pattern and induces intracellular aggregation of the TJ proteins zonlua occludens protein 1, as well as claudins. Furthermore, IL-13 treatment increases expression of ubiquitin conjugating E2 enzyme UBE2Z. Co-localization and proximity ligation assays further showed that ubiquitin and the proteasomal marker PSMA5 co-localize with TJ proteins in IL-13 treated cells, showing that TJ proteins are ubiquitinated following IL-13 exposure. UBE2Z upregulation occurs within the first day after IL-13 exposure. Proteasomal aggregation of ubiquitinated TJ proteins starts three days after IL-13 exposure and transepithelial electrical resistance (TEER) decrease follows the time course of TJ-protein aggregation. Inhibition of JAK/STAT signaling abolishes IL-13 induced effects. Our data suggest that that IL-13 induces ubiquitination and proteasomal aggregation of TJ proteins via JAK/STAT dependent expression of UBE2Z, resulting in opening of TJs. This may contribute to barrier disturbances in pulmonary epithelia and lung damage of patients with inflammatory lung diseases. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

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12 pages, 1444 KiB

Open AccessArticle

Intestinal Preservation Injury: A Comparison Between Rat, Porcine and Human Intestines

by John Mackay Søfteland, Anna Casselbrant, Ali-Reza Biglarnia, Johan Linders, Mats Hellström, Antonio Pesce, Arvind Manikantan Padma, Lucian Petru Jiga, Bogdan Hoinoiu, Mihai Ionac and Mihai Oltean

Int. J. Mol. Sci. 2019, 20(13), 3135; https://doi.org/10.3390/ijms20133135 - 27 Jun 2019

Cited by 17 | Viewed by 3926

Abstract

Advanced preservation injury (PI) after intestinal transplantation has deleterious short- and long-term effects and constitutes a major research topic. Logistics and costs favor rodent studies, whereas clinical translation mandates studies in larger animals or using human material. Despite diverging reports, no direct comparison [...] Read more.

Advanced preservation injury (PI) after intestinal transplantation has deleterious short- and long-term effects and constitutes a major research topic. Logistics and costs favor rodent studies, whereas clinical translation mandates studies in larger animals or using human material. Despite diverging reports, no direct comparison between the development of intestinal PI in rats, pigs, and humans is available. We compared the development of PI in rat, porcine, and human intestines. Intestinal procurement and cold storage (CS) using histidine–tryptophan–ketoglutarate solution was performed in rats, pigs, and humans. Tissue samples were obtained after 8, 14, and 24 h of CS), and PI was assessed morphologically and at the molecular level (cleaved caspase-3, zonula occludens, claudin-3 and 4, tricellulin, occludin, cytokeratin-8) using immunohistochemistry and Western blot. Intestinal PI developed slower in pigs compared to rats and humans. Tissue injury and apoptosis were significantly higher in rats. Tight junction proteins showed quantitative and qualitative changes differing between species. Significant interspecies differences exist between rats, pigs, and humans regarding intestinal PI progression at tissue and molecular levels. These differences should be taken into account both with regards to study design and the interpretation of findings when relating them to the clinical setting. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

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11 pages, 1963 KiB

Open AccessArticle

Caprate Modulates Intestinal Barrier Function in Porcine Peyer’s Patch Follicle-Associated Epithelium

by Judith Radloff, Valeria Cornelius, Alexander G. Markov and Salah Amasheh

Int. J. Mol. Sci. 2019, 20(6), 1418; https://doi.org/10.3390/ijms20061418 - 20 Mar 2019

Cited by 12 | Viewed by 3403

Abstract

Background: Many food components influence intestinal epithelial barrier properties and might therefore also affect susceptibility to the development of food allergies. Such allergies are triggered by increased antibody production initiated in Peyer’s patches (PP). Usually, the presentation of antigens in the lumen of [...] Read more.

Background: Many food components influence intestinal epithelial barrier properties and might therefore also affect susceptibility to the development of food allergies. Such allergies are triggered by increased antibody production initiated in Peyer’s patches (PP). Usually, the presentation of antigens in the lumen of the gut to the immune cells of the PP is strongly regulated by the follicle-associated epithelium (FAE) that covers the PP. As the food component caprate has been shown to impede barrier properties in villous epithelium, we hypothesized that caprate also affects the barrier function of the PP FAE, thereby possibly contributing a risk factor for the development of food allergies. Methods: In this study, we have focused on the effects of caprate on the barrier function of PP, employing in vitro and ex vivo experimental setups to investigate functional and molecular barrier properties. Incubation with caprate induced an increase of transepithelial resistance, and a marked increase of permeability for the paracellular marker fluorescein in porcine PP to 180% of control values. These effects are in accordance with changes in the expression levels of the barrier-forming tight junction proteins tricellulin and claudin-5. Conclusions: This barrier-affecting mechanism could be involved in the initial steps of a food allergy, since it might trigger unregulated contact of the gut lumen with antigens. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

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Review

Jump to: Editorial, Research

17 pages, 1960 KiB

Open AccessReview

Contributions of Myosin Light Chain Kinase to Regulation of Epithelial Paracellular Permeability and Mucosal Homeostasis

by Wei-Qi He, Jing Wang, Jian-Ying Sheng, Juan-Min Zha, W. Vallen Graham and Jerrold R. Turner

Int. J. Mol. Sci. 2020, 21(3), 993; https://doi.org/10.3390/ijms21030993 - 3 Feb 2020

Cited by 88 | Viewed by 10054

Abstract

Intestinal barrier function is required for the maintenance of mucosal homeostasis. Barrier dysfunction is thought to promote progression of both intestinal and systemic diseases. In many cases, this barrier loss reflects increased permeability of the paracellular tight junction as a consequence of myosin [...] Read more.

Intestinal barrier function is required for the maintenance of mucosal homeostasis. Barrier dysfunction is thought to promote progression of both intestinal and systemic diseases. In many cases, this barrier loss reflects increased permeability of the paracellular tight junction as a consequence of myosin light chain kinase (MLCK) activation and myosin II regulatory light chain (MLC) phosphorylation. Although some details about MLCK activation remain to be defined, it is clear that this triggers perijunctional actomyosin ring (PAMR) contraction that leads to molecular reorganization of tight junction structure and composition, including occludin endocytosis. In disease states, this process can be triggered by pro-inflammatory cytokines including tumor necrosis factor-α (TNF), interleukin-1β (IL-1β), and several related molecules. Of these, TNF has been studied in the greatest detail and is known to activate long MLCK transcription, expression, enzymatic activity, and recruitment to the PAMR. Unfortunately, toxicities associated with inhibition of MLCK expression or enzymatic activity make these unsuitable as therapeutic targets. Recent work has, however, identified a small molecule that prevents MLCK1 recruitment to the PAMR without inhibiting enzymatic function. This small molecule, termed Divertin, restores barrier function after TNF-induced barrier loss and prevents disease progression in experimental chronic inflammatory bowel disease. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

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11 pages, 650 KiB

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The Integral Role of Tight Junction Proteins in the Repair of Injured Intestinal Epithelium

by Zachary M. Slifer and Anthony T. Blikslager

Int. J. Mol. Sci. 2020, 21(3), 972; https://doi.org/10.3390/ijms21030972 - 1 Feb 2020

Cited by 141 | Viewed by 9945

Abstract

The intestinal epithelial monolayer forms a transcellular and paracellular barrier that separates luminal contents from the interstitium. The paracellular barrier consists of a highly organized complex of intercellular junctions that is primarily regulated by apical tight junction proteins and tight junction-associated proteins. This [...] Read more.

The intestinal epithelial monolayer forms a transcellular and paracellular barrier that separates luminal contents from the interstitium. The paracellular barrier consists of a highly organized complex of intercellular junctions that is primarily regulated by apical tight junction proteins and tight junction-associated proteins. This homeostatic barrier can be lost through a multitude of injurious events that cause the disruption of the tight junction complex. Acute repair after injury leading to the reestablishment of the tight junction barrier is crucial for the return of both barrier function as well as other cellular functions, including water regulation and nutrient absorption. This review provides an overview of the tight junction complex components and how they link to other plasmalemmal proteins, such as ion channels and transporters, to induce tight junction closure during repair of acute injury. Understanding the components of interepithelial tight junctions and the mechanisms of tight junction regulation after injury is crucial for developing future therapeutic targets for patients experiencing dysregulated intestinal permeability. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

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23 pages, 1113 KiB

Open AccessReview

Tight Junction Proteins and the Biology of Hepatobiliary Disease

by Natascha Roehlen, Armando Andres Roca Suarez, Houssein El Saghire, Antonio Saviano, Catherine Schuster, Joachim Lupberger and Thomas F. Baumert

Int. J. Mol. Sci. 2020, 21(3), 825; https://doi.org/10.3390/ijms21030825 - 28 Jan 2020

Cited by 50 | Viewed by 9108

Abstract

Tight junctions (TJ) are intercellular adhesion complexes on epithelial cells and composed of integral membrane proteins as well as cytosolic adaptor proteins. Tight junction proteins have been recognized to play a key role in health and disease. In the liver, TJ proteins have [...] Read more.

Tight junctions (TJ) are intercellular adhesion complexes on epithelial cells and composed of integral membrane proteins as well as cytosolic adaptor proteins. Tight junction proteins have been recognized to play a key role in health and disease. In the liver, TJ proteins have several functions: they contribute as gatekeepers for paracellular diffusion between adherent hepatocytes or cholangiocytes to shape the blood-biliary barrier (BBIB) and maintain tissue homeostasis. At non-junctional localizations, TJ proteins are involved in key regulatory cell functions such as differentiation, proliferation, and migration by recruiting signaling proteins in response to extracellular stimuli. Moreover, TJ proteins are hepatocyte entry factors for the hepatitis C virus (HCV)—a major cause of liver disease and cancer worldwide. Perturbation of TJ protein expression has been reported in chronic HCV infection, cholestatic liver diseases as well as hepatobiliary carcinoma. Here we review the physiological function of TJ proteins in the liver and their implications in hepatobiliary diseases. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

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15 pages, 24735 KiB

Open AccessReview

Super-Resolution Imaging of Tight and Adherens Junctions: Challenges and Open Questions

by Hannes Gonschior, Volker Haucke and Martin Lehmann

Int. J. Mol. Sci. 2020, 21(3), 744; https://doi.org/10.3390/ijms21030744 - 23 Jan 2020

Cited by 17 | Viewed by 6200

Abstract

The tight junction (TJ) and the adherens junction (AJ) bridge the paracellular cleft of epithelial and endothelial cells. In addition to their role as protective barriers against bacteria and their toxins they maintain ion homeostasis, cell polarity, and mechano-sensing. Their functional loss leads [...] Read more.

The tight junction (TJ) and the adherens junction (AJ) bridge the paracellular cleft of epithelial and endothelial cells. In addition to their role as protective barriers against bacteria and their toxins they maintain ion homeostasis, cell polarity, and mechano-sensing. Their functional loss leads to pathological changes such as tissue inflammation, ion imbalance, and cancer. To better understand the consequences of such malfunctions, the junctional nanoarchitecture is of great importance since it remains so far largely unresolved, mainly because of major difficulties in dynamically imaging these structures at sufficient resolution and with molecular precision. The rapid development of super-resolution imaging techniques ranging from structured illumination microscopy (SIM), stimulated emission depletion (STED) microscopy, and single molecule localization microscopy (SMLM) has now enabled molecular imaging of biological specimens from cells to tissues with nanometer resolution. Here we summarize these techniques and their application to the dissection of the nanoscale molecular architecture of TJs and AJs. We propose that super-resolution imaging together with advances in genome engineering and functional analyses approaches will create a leap in our understanding of the composition, assembly, and function of TJs and AJs at the nanoscale and, thereby, enable a mechanistic understanding of their dysfunction in disease. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

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12 pages, 7050 KiB

Open AccessReview

Computational Modeling of Claudin Structure and Function

by Shadi Fuladi, Ridaka-Wal Jannat, Le Shen, Christopher R. Weber and Fatemeh Khalili-Araghi

Int. J. Mol. Sci. 2020, 21(3), 742; https://doi.org/10.3390/ijms21030742 - 23 Jan 2020

Cited by 12 | Viewed by 4255

Abstract

Tight junctions form a barrier to control passive transport of ions and small molecules across epithelia and endothelia. In addition to forming a barrier, some of claudins control transport properties of tight junctions by forming charge- and size-selective ion channels. It has been [...] Read more.

Tight junctions form a barrier to control passive transport of ions and small molecules across epithelia and endothelia. In addition to forming a barrier, some of claudins control transport properties of tight junctions by forming charge- and size-selective ion channels. It has been suggested claudin monomers can form or incorporate into tight junction strands to form channels. Resolving the crystallographic structure of several claudins in recent years has provided an opportunity to examine structural basis of claudins in tight junctions. Computational and theoretical modeling relying on atomic description of the pore have contributed significantly to our understanding of claudin pores and paracellular transport. In this paper, we review recent computational and mathematical modeling of claudin barrier function. We focus on dynamic modeling of global epithelial barrier function as a function of claudin pores and molecular dynamics studies of claudins leading to a functional model of claudin channels. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

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19 pages, 1592 KiB

Open AccessReview

Cerebral Cavernous Malformation Proteins in Barrier Maintenance and Regulation

by Shu Wei, Ye Li, Sean P. Polster, Christopher R. Weber, Issam A. Awad and Le Shen

Int. J. Mol. Sci. 2020, 21(2), 675; https://doi.org/10.3390/ijms21020675 - 20 Jan 2020

Cited by 24 | Viewed by 9269

Abstract

Cerebral cavernous malformation (CCM) is a disease characterized by mulberry shaped clusters of dilated microvessels, primarily in the central nervous system. Such lesions can cause seizures, headaches, and stroke from brain bleeding. Loss-of-function germline and somatic mutations of a group of genes, called [...] Read more.

Cerebral cavernous malformation (CCM) is a disease characterized by mulberry shaped clusters of dilated microvessels, primarily in the central nervous system. Such lesions can cause seizures, headaches, and stroke from brain bleeding. Loss-of-function germline and somatic mutations of a group of genes, called CCM genes, have been attributed to disease pathogenesis. In this review, we discuss the impact of CCM gene encoded proteins on cellular signaling, barrier function of endothelium and epithelium, and their contribution to CCM and potentially other diseases. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

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24 pages, 3584 KiB

Open AccessReview

Claudin-1, A Double-Edged Sword in Cancer

by Ajaz A. Bhat, Najeeb Syed, Lubna Therachiyil, Sabah Nisar, Sheema Hashem, Muzafar A. Macha, Santosh K. Yadav, Roopesh Krishnankutty, Shanmugakonar Muralitharan, Hamda Al-Naemi, Puneet Bagga, Ravinder Reddy, Punita Dhawan, Anthony Akobeng, Shahab Uddin, Michael P. Frenneaux, Wael El-Rifai and Mohammad Haris

Int. J. Mol. Sci. 2020, 21(2), 569; https://doi.org/10.3390/ijms21020569 - 15 Jan 2020

Cited by 95 | Viewed by 11583

Abstract

Claudins, a group of membrane proteins involved in the formation of tight junctions, are mainly found in endothelial or epithelial cells. These proteins have attracted much attention in recent years and have been implicated and studied in a multitude of diseases. Claudins not [...] Read more.

Claudins, a group of membrane proteins involved in the formation of tight junctions, are mainly found in endothelial or epithelial cells. These proteins have attracted much attention in recent years and have been implicated and studied in a multitude of diseases. Claudins not only regulate paracellular transepithelial/transendothelial transport but are also critical for cell growth and differentiation. Not only tissue-specific but the differential expression in malignant tumors is also the focus of claudin-related research. In addition to up- or down-regulation, claudin proteins also undergo delocalization, which plays a vital role in tumor invasion and aggressiveness. Claudin (CLDN)-1 is the most-studied claudin in cancers and to date, its role as either a tumor promoter or suppressor (or both) is not established. In some cancers, lower expression of CLDN-1 is shown to be associated with cancer progression and invasion, while in others, loss of CLDN-1 improves the patient survival. Another topic of discussion regarding the significance of CLDN-1 is its localization (nuclear or cytoplasmic vs perijunctional) in diseased states. This article reviews the evidence regarding CLDN-1 in cancers either as a tumor promoter or suppressor from the literature and we also review the literature regarding the pattern of CLDN-1 distribution in different cancers, focusing on whether this localization is associated with tumor aggressiveness. Furthermore, we utilized expression data from The Cancer Genome Atlas (TCGA) to investigate the association between CLDN-1 expression and overall survival (OS) in different cancer types. We also used TCGA data to compare CLDN-1 expression in normal and tumor tissues. Additionally, a pathway interaction analysis was performed to investigate the interaction of CLDN-1 with other proteins and as a future therapeutic target. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

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11 pages, 1271 KiB

Open AccessReview

Claudins in the Renal Collecting Duct

by Janna Leiz and Kai M. Schmidt-Ott

Int. J. Mol. Sci. 2020, 21(1), 221; https://doi.org/10.3390/ijms21010221 - 28 Dec 2019

Cited by 11 | Viewed by 15211

Abstract

The renal collecting duct fine-tunes urinary composition, and thereby, coordinates key physiological processes, such as volume/blood pressure regulation, electrolyte-free water reabsorption, and acid-base homeostasis. The collecting duct epithelium is comprised of a tight epithelial barrier resulting in a strict separation of intraluminal urine [...] Read more.

The renal collecting duct fine-tunes urinary composition, and thereby, coordinates key physiological processes, such as volume/blood pressure regulation, electrolyte-free water reabsorption, and acid-base homeostasis. The collecting duct epithelium is comprised of a tight epithelial barrier resulting in a strict separation of intraluminal urine and the interstitium. Tight junctions are key players in enforcing this barrier and in regulating paracellular transport of solutes across the epithelium. The features of tight junctions across different epithelia are strongly determined by their molecular composition. Claudins are particularly important structural components of tight junctions because they confer barrier and transport properties. In the collecting duct, a specific set of claudins (Cldn-3, Cldn-4, Cldn-7, Cldn-8) is expressed, and each of these claudins has been implicated in mediating aspects of the specific properties of its tight junction. The functional disruption of individual claudins or of the overall barrier function results in defects of blood pressure and water homeostasis. In this concise review, we provide an overview of the current knowledge on the role of the collecting duct epithelial barrier and of claudins in collecting duct function and pathophysiology. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

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12 pages, 620 KiB

Open AccessReview

Tight Junctions of the Outer Blood Retina Barrier

by Aisling Naylor, Alan Hopkins, Natalie Hudson and Matthew Campbell

Int. J. Mol. Sci. 2020, 21(1), 211; https://doi.org/10.3390/ijms21010211 - 27 Dec 2019

Cited by 122 | Viewed by 14570

Abstract

The outer blood retina barrier (oBRB) formed by the retinal pigment epithelium (RPE) is critical for maintaining retinal homeostasis. Critical to this modified neuro-epithelial barrier is the presence of the tight junction structure that is formed at the apical periphery of contacting cells. [...] Read more.

The outer blood retina barrier (oBRB) formed by the retinal pigment epithelium (RPE) is critical for maintaining retinal homeostasis. Critical to this modified neuro-epithelial barrier is the presence of the tight junction structure that is formed at the apical periphery of contacting cells. This tight junction complex mediates size-selective passive diffusion of solutes to and from the outer segments of the retina. Unlike other epithelial cells, the apical surface of the RPE is in direct contact with neural tissue and it is centrally involved in the daily phagocytosis of the effete tips of photoreceptor cells. While much is known about the intracellular trafficking of material within the RPE, less is known about the role of the tight junction complexes in health and diseased states. Here, we provide a succinct overview of the molecular composition of the RPE tight junction complex in addition to highlighting some of the most common retinopathies that involve a dysregulation of RPE integrity Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

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21 pages, 3969 KiB

Open AccessReview

Role of Claudin Proteins in Regulating Cancer Stem Cells and Chemoresistance-Potential Implication in Disease Prognosis and Therapy

by Saiprasad Gowrikumar, Amar B. Singh and Punita Dhawan

Int. J. Mol. Sci. 2020, 21(1), 53; https://doi.org/10.3390/ijms21010053 - 20 Dec 2019

Cited by 46 | Viewed by 8624

Abstract

Claudins are cell–cell adhesion proteins, which are expressed in tight junctions (TJs), the most common apical cell-cell adhesion. Claudin proteins help to regulate defense and barrier functions, as well as differentiation and polarity in epithelial and endothelial cells. A series of studies have [...] Read more.

Claudins are cell–cell adhesion proteins, which are expressed in tight junctions (TJs), the most common apical cell-cell adhesion. Claudin proteins help to regulate defense and barrier functions, as well as differentiation and polarity in epithelial and endothelial cells. A series of studies have now reported dysregulation of claudin proteins in cancers. However, the precise mechanisms are still not well understood. Nonetheless, studies have clearly demonstrated a causal role of multiple claudins in the regulation of epithelial to mesenchymal transition (EMT), a key feature in the acquisition of a cancer stem cell phenotype in cancer cells. In addition, claudin proteins are known to modulate therapy resistance in cancer cells, a feature associated with cancer stem cells. In this review, we have focused primarily on highlighting the causal link between claudins, cancer stem cells, and therapy resistance. We have also contemplated the significance of claudins as novel targets in improving the efficacy of cancer therapy. Overall, this review provides a much-needed understanding of the emerging role of claudin proteins in cancer malignancy and therapeutic management. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

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24 pages, 5397 KiB

Open AccessReview

Structural Features of Tight-Junction Proteins

by Udo Heinemann and Anja Schuetz

Int. J. Mol. Sci. 2019, 20(23), 6020; https://doi.org/10.3390/ijms20236020 - 29 Nov 2019

Cited by 124 | Viewed by 12396

Abstract

Tight junctions are complex supramolecular entities composed of integral membrane proteins, membrane-associated and soluble cytoplasmic proteins engaging in an intricate and dynamic system of protein–protein interactions. Three-dimensional structures of several tight-junction proteins or their isolated domains have been determined by X-ray crystallography, nuclear [...] Read more.

Tight junctions are complex supramolecular entities composed of integral membrane proteins, membrane-associated and soluble cytoplasmic proteins engaging in an intricate and dynamic system of protein–protein interactions. Three-dimensional structures of several tight-junction proteins or their isolated domains have been determined by X-ray crystallography, nuclear magnetic resonance spectroscopy, and cryo-electron microscopy. These structures provide direct insight into molecular interactions that contribute to the formation, integrity, or function of tight junctions. In addition, the known experimental structures have allowed the modeling of ligand-binding events involving tight-junction proteins. Here, we review the published structures of tight-junction proteins. We show that these proteins are composed of a limited set of structural motifs and highlight common types of interactions between tight-junction proteins and their ligands involving these motifs. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

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18 pages, 2578 KiB

Open AccessReview

Reciprocal Association between the Apical Junctional Complex and AMPK: A Promising Therapeutic Target for Epithelial/Endothelial Barrier Function?

by Kazuto Tsukita, Tomoki Yano, Atsushi Tamura and Sachiko Tsukita

Int. J. Mol. Sci. 2019, 20(23), 6012; https://doi.org/10.3390/ijms20236012 - 29 Nov 2019

Cited by 18 | Viewed by 6703

Abstract

Epithelial/endothelial cells adhere to each other via cell–cell junctions including tight junctions (TJs) and adherens junctions (AJs). TJs and AJs are spatiotemporally and functionally integrated, and are thus often collectively defined as apical junctional complexes (AJCs), regulating a number of spatiotemporal events including [...] Read more.

Epithelial/endothelial cells adhere to each other via cell–cell junctions including tight junctions (TJs) and adherens junctions (AJs). TJs and AJs are spatiotemporally and functionally integrated, and are thus often collectively defined as apical junctional complexes (AJCs), regulating a number of spatiotemporal events including paracellular barrier, selective permeability, apicobasal cell polarity, mechano-sensing, intracellular signaling cascades, and epithelial morphogenesis. Over the past 15 years, it has been acknowledged that adenosine monophosphate (AMP)-activated protein kinase (AMPK), a well-known central regulator of energy metabolism, has a reciprocal association with AJCs. Here, we review the current knowledge of this association and show the following evidences: (1) as an upstream regulator, AJs activate the liver kinase B1 (LKB1)–AMPK axis particularly in response to applied junctional tension, and (2) TJ function and apicobasal cell polarization are downstream targets of AMPK and are promoted by AMPK activation. Although molecular mechanisms underlying these phenomena have not yet been completely elucidated, identifications of novel AMPK effectors in AJCs and AMPK-driven epithelial transcription factors have enhanced our knowledge. More intensive studies along this line would eventually lead to the development of AMPK-based therapies, enabling us to manipulate epithelial/endothelial barrier function. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

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30 pages, 3922 KiB

Open AccessReview

Tight Junctions in Cell Proliferation

by Mónica Díaz-Coránguez, Xuwen Liu and David A. Antonetti

Int. J. Mol. Sci. 2019, 20(23), 5972; https://doi.org/10.3390/ijms20235972 - 27 Nov 2019

Cited by 61 | Viewed by 10927

Abstract

Tight junction (TJ) proteins form a continuous intercellular network creating a barrier with selective regulation of water, ion, and solutes across endothelial, epithelial, and glial tissues. TJ proteins include the claudin family that confers barrier properties, members of the MARVEL family that contribute [...] Read more.

Tight junction (TJ) proteins form a continuous intercellular network creating a barrier with selective regulation of water, ion, and solutes across endothelial, epithelial, and glial tissues. TJ proteins include the claudin family that confers barrier properties, members of the MARVEL family that contribute to barrier regulation, and JAM molecules, which regulate junction organization and diapedesis. In addition, the membrane-associated proteins such as MAGUK family members, i.e., zonula occludens, form the scaffold linking the transmembrane proteins to both cell signaling molecules and the cytoskeleton. Most studies of TJ have focused on the contribution to cell-cell adhesion and tissue barrier properties. However, recent studies reveal that, similar to adherens junction proteins, TJ proteins contribute to the control of cell proliferation. In this review, we will summarize and discuss the specific role of TJ proteins in the control of epithelial and endothelial cell proliferation. In some cases, the TJ proteins act as a reservoir of critical cell cycle modulators, by binding and regulating their nuclear access, while in other cases, junctional proteins are located at cellular organelles, regulating transcription and proliferation. Collectively, these studies reveal that TJ proteins contribute to the control of cell proliferation and differentiation required for forming and maintaining a tissue barrier. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

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27 pages, 1068 KiB

Open AccessReview

Claudin-2: Roles beyond Permeability Functions

by Shruthi Venugopal, Shaista Anwer and Katalin Szászi

Int. J. Mol. Sci. 2019, 20(22), 5655; https://doi.org/10.3390/ijms20225655 - 12 Nov 2019

Cited by 82 | Viewed by 10990

Abstract

Claudin-2 is expressed in the tight junctions of leaky epithelia, where it forms cation-selective and water permeable paracellular channels. Its abundance is under fine control by a complex signaling network that affects both its synthesis and turnover in response to various environmental inputs. [...] Read more.

Claudin-2 is expressed in the tight junctions of leaky epithelia, where it forms cation-selective and water permeable paracellular channels. Its abundance is under fine control by a complex signaling network that affects both its synthesis and turnover in response to various environmental inputs. Claudin-2 expression is dysregulated in many pathologies including cancer, inflammation, and fibrosis. Claudin-2 has a key role in energy-efficient ion and water transport in the proximal tubules of the kidneys and in the gut. Importantly, strong evidence now also supports a role for this protein as a modulator of vital cellular events relevant to diseases. Signaling pathways that are overactivated in diseases can alter claudin-2 expression, and a good correlation exists between disease stage and claudin-2 abundance. Further, loss- and gain-of-function studies showed that primary changes in claudin-2 expression impact vital cellular processes such as proliferation, migration, and cell fate determination. These effects appear to be mediated by alterations in key signaling pathways. The specific mechanisms linking claudin-2 to these changes remain poorly understood, but adapters binding to the intracellular portion of claudin-2 may play a key role. Thus, dysregulation of claudin-2 may contribute to the generation, maintenance, and/or progression of diseases through both permeability-dependent and -independent mechanisms. The aim of this review is to provide an overview of the properties, regulation, and functions of claudin-2, with a special emphasis on its signal-modulating effects and possible role in diseases. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

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30 pages, 5667 KiB

Open AccessReview

Computational Nanoscopy of Tight Junctions at the Blood–Brain Barrier Interface

by Nandhini Rajagopal, Flaviyan Jerome Irudayanathan and Shikha Nangia

Int. J. Mol. Sci. 2019, 20(22), 5583; https://doi.org/10.3390/ijms20225583 - 8 Nov 2019

Cited by 19 | Viewed by 10169

Abstract

The selectivity of the blood–brain barrier (BBB) is primarily maintained by tight junctions (TJs), which act as gatekeepers of the paracellular space by blocking blood-borne toxins, drugs, and pathogens from entering the brain. The BBB presents a significant challenge in designing neurotherapeutics, so [...] Read more.

The selectivity of the blood–brain barrier (BBB) is primarily maintained by tight junctions (TJs), which act as gatekeepers of the paracellular space by blocking blood-borne toxins, drugs, and pathogens from entering the brain. The BBB presents a significant challenge in designing neurotherapeutics, so a comprehensive understanding of the TJ architecture can aid in the design of novel therapeutics. Unraveling the intricacies of TJs with conventional experimental techniques alone is challenging, but recently developed computational tools can provide a valuable molecular-level understanding of TJ architecture. We employed the computational methods toolkit to investigate claudin-5, a highly expressed TJ protein at the BBB interface. Our approach started with the prediction of claudin-5 structure, evaluation of stable dimer conformations and nanoscale assemblies, followed by the impact of lipid environments, and posttranslational modifications on these claudin-5 assemblies. These led to the study of TJ pores and barriers and finally understanding of ion and small molecule transport through the TJs. Some of these in silico, molecular-level findings, will need to be corroborated by future experiments. The resulting understanding can be advantageous towards the eventual goal of drug delivery across the BBB. This review provides key insights gleaned from a series of state-of-the-art nanoscale simulations (or computational nanoscopy studies) performed on the TJ architecture. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

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20 pages, 2510 KiB

Open AccessReview

Mouse Models of Human Claudin-Associated Disorders: Benefits and Limitations

by Murat Seker, Cármen Fernández-Rodríguez, Luis Alfonso Martínez-Cruz and Dominik Müller

Int. J. Mol. Sci. 2019, 20(21), 5504; https://doi.org/10.3390/ijms20215504 - 5 Nov 2019

Cited by 10 | Viewed by 4203

Abstract

In higher organisms, epithelia separate compartments in order to guarantee their proper function. Such structures are able to seal but also to allow substances to pass. Within the paracellular pathway, a supramolecular structure, the tight junction transport is largely controlled by the temporospatial [...] Read more.

In higher organisms, epithelia separate compartments in order to guarantee their proper function. Such structures are able to seal but also to allow substances to pass. Within the paracellular pathway, a supramolecular structure, the tight junction transport is largely controlled by the temporospatial regulation of its major protein family called claudins. Besides the fact that the expression of claudins has been identified in different forms of human diseases like cancer, clearly defined mutations in the corresponding claudin genes have been shown to cause distinct human disorders. Such disorders comprise the skin and its adjacent structures, liver, kidney, the inner ear, and the eye. From the phenotype analysis, it has also become clear that different claudins can cause a complex phenotype when expressed in different organs. To gain deeper insights into the physiology and pathophysiology of claudin-associated disorders, several mouse models have been generated. In order to model human disorders in detail, they have been designed either as full knockouts, knock-downs or knock-ins by a variety of techniques. Here, we review human disorders caused by CLDN mutations and their corresponding mouse models that have been generated thus far and assess their usefulness as a model for the corresponding human disorder. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

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28 pages, 326 KiB

Open AccessReview

The Blood–Brain Barrier and Its Intercellular Junctions in Age-Related Brain Disorders

by Laura Costea, Ádám Mészáros, Hannelore Bauer, Hans-Christian Bauer, Andreas Traweger, Imola Wilhelm, Attila E. Farkas and István A. Krizbai

Int. J. Mol. Sci. 2019, 20(21), 5472; https://doi.org/10.3390/ijms20215472 - 3 Nov 2019

Cited by 72 | Viewed by 6364

Abstract

With age, our cognitive skills and abilities decline. Maybe starting as an annoyance, this decline can become a major impediment to normal daily life. Recent research shows that the neurodegenerative disorders responsible for age associated cognitive dysfunction are mechanistically linked to the state [...] Read more.

With age, our cognitive skills and abilities decline. Maybe starting as an annoyance, this decline can become a major impediment to normal daily life. Recent research shows that the neurodegenerative disorders responsible for age associated cognitive dysfunction are mechanistically linked to the state of the microvasculature in the brain. When the microvasculature does not function properly, ischemia, hypoxia, oxidative stress and related pathologic processes ensue, further damaging vascular and neural function. One of the most important and specialized functions of the brain microvasculature is the blood–brain barrier (BBB), which controls the movement of molecules between blood circulation and the brain parenchyma. In this review, we are focusing on tight junctions (TJs), the multiprotein complexes that play an important role in establishing and maintaining barrier function. After a short introduction of the cell types that modulate barrier function via intercellular communication, we examine how age, age related pathologies and the aging of the immune system affects TJs. Then, we review how the TJs are affected in age associated neurodegenerative disorders: Alzheimer’s disease and Parkinson’s disease. Lastly, we summarize the TJ aspects of Huntington’s disease and schizophrenia. Barrier dysfunction appears to be a common denominator in neurological disorders, warranting detailed research into the molecular mechanisms behind it. Learning the commonalities and differences in the pathomechanism of the BBB injury in different neurological disorders will predictably lead to development of new therapeutics that improve our life as we age. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

15 pages, 1149 KiB

Open AccessReview

A Novel Claudinopathy Based on Claudin-10 Mutations

by Susanne Milatz

Int. J. Mol. Sci. 2019, 20(21), 5396; https://doi.org/10.3390/ijms20215396 - 30 Oct 2019

Cited by 27 | Viewed by 4143

Abstract

Claudins are key components of the tight junction, sealing the paracellular cleft or composing size-, charge- and water-selective paracellular channels. Claudin-10 occurs in two major isoforms, claudin-10a and claudin-10b, which constitute paracellular anion or cation channels, respectively. For several years after the discovery [...] Read more.

Claudins are key components of the tight junction, sealing the paracellular cleft or composing size-, charge- and water-selective paracellular channels. Claudin-10 occurs in two major isoforms, claudin-10a and claudin-10b, which constitute paracellular anion or cation channels, respectively. For several years after the discovery of claudin-10, its functional relevance in men has remained elusive. Within the past two years, several studies appeared, describing patients with different pathogenic variants of the CLDN10 gene. Patients presented with dysfunction of kidney, exocrine glands and skin. This review summarizes and compares the recently published studies reporting on a novel autosomal-recessive disorder based on claudin-10 mutations. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

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27 pages, 3355 KiB

Open AccessReview

Structure and Junctional Complexes of Endothelial, Epithelial and Glial Brain Barriers

by Mariana Castro Dias, Josephine A. Mapunda, Mykhailo Vladymyrov and Britta Engelhardt

Int. J. Mol. Sci. 2019, 20(21), 5372; https://doi.org/10.3390/ijms20215372 - 29 Oct 2019

Cited by 111 | Viewed by 13764

Abstract

The homeostasis of the central nervous system (CNS) is ensured by the endothelial, epithelial, mesothelial and glial brain barriers, which strictly control the passage of molecules, solutes and immune cells. While the endothelial blood-brain barrier (BBB) and the epithelial blood-cerebrospinal fluid barrier (BCSFB) [...] Read more.

The homeostasis of the central nervous system (CNS) is ensured by the endothelial, epithelial, mesothelial and glial brain barriers, which strictly control the passage of molecules, solutes and immune cells. While the endothelial blood-brain barrier (BBB) and the epithelial blood-cerebrospinal fluid barrier (BCSFB) have been extensively investigated, less is known about the epithelial and mesothelial arachnoid barrier and the glia limitans. Here, we summarize current knowledge of the cellular composition of the brain barriers with a specific focus on describing the molecular constituents of their junctional complexes. We propose that the brain barriers maintain CNS immune privilege by dividing the CNS into compartments that differ with regard to their role in immune surveillance of the CNS. We close by providing a brief overview on experimental tools allowing for reliable in vivo visualization of the brain barriers and their junctional complexes and thus the respective CNS compartments. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

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24 pages, 3473 KiB

Open AccessReview

ZO-2 Is a Master Regulator of Gene Expression, Cell Proliferation, Cytoarchitecture, and Cell Size

by Lorenza González-Mariscal, Helios Gallego-Gutiérrez, Laura González-González and Christian Hernández-Guzmán

Int. J. Mol. Sci. 2019, 20(17), 4128; https://doi.org/10.3390/ijms20174128 - 24 Aug 2019

Cited by 35 | Viewed by 9538

Abstract

ZO-2 is a cytoplasmic protein of tight junctions (TJs). Here, we describe ZO-2 involvement in the formation of the apical junctional complex during early development and in TJ biogenesis in epithelial cultured cells. ZO-2 acts as a scaffold for the polymerization of claudins [...] Read more.

ZO-2 is a cytoplasmic protein of tight junctions (TJs). Here, we describe ZO-2 involvement in the formation of the apical junctional complex during early development and in TJ biogenesis in epithelial cultured cells. ZO-2 acts as a scaffold for the polymerization of claudins at TJs and plays a unique role in the blood–testis barrier, as well as at TJs of the human liver and the inner ear. ZO-2 movement between the cytoplasm and nucleus is regulated by nuclear localization and exportation signals and post-translation modifications, while ZO-2 arrival at the cell border is triggered by activation of calcium sensing receptors and corresponding downstream signaling. Depending on its location, ZO-2 associates with junctional proteins and the actomyosin cytoskeleton or a variety of nuclear proteins, playing a role as a transcriptional repressor that leads to inhibition of cell proliferation and transformation. ZO-2 regulates cell architecture through modulation of Rho proteins and its absence induces hypertrophy due to inactivation of the Hippo pathway and activation of mTOR and S6K. The interaction of ZO-2 with viral oncoproteins and kinases and its silencing in diverse carcinomas reinforce the view of ZO-2 as a tumor regulator protein. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

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17 pages, 1902 KiB

Open AccessReview

Potential for Tight Junction Protein–Directed Drug Development Using Claudin Binders and Angubindin-1

by Yosuke Hashimoto, Keisuke Tachibana, Susanne M. Krug, Jun Kunisawa, Michael Fromm and Masuo Kondoh

Int. J. Mol. Sci. 2019, 20(16), 4016; https://doi.org/10.3390/ijms20164016 - 17 Aug 2019

Cited by 31 | Viewed by 6426

Abstract

The tight junction (TJ) is an intercellular sealing component found in epithelial and endothelial tissues that regulates the passage of solutes across the paracellular space. Research examining the biology of TJs has revealed that they are complex biochemical structures constructed from a range [...] Read more.

The tight junction (TJ) is an intercellular sealing component found in epithelial and endothelial tissues that regulates the passage of solutes across the paracellular space. Research examining the biology of TJs has revealed that they are complex biochemical structures constructed from a range of proteins including claudins, occludin, tricellulin, angulins and junctional adhesion molecules. The transient disruption of the barrier function of TJs to open the paracellular space is one means of enhancing mucosal and transdermal drug absorption and to deliver drugs across the blood–brain barrier. However, the disruption of TJs can also open the paracellular space to harmful xenobiotics and pathogens. To address this issue, the strategies targeting TJ proteins have been developed to loosen TJs in a size- or tissue-dependent manner rather than to disrupt them. As several TJ proteins are overexpressed in malignant tumors and in the inflamed intestinal tract, and are present in cells and epithelia conjoined with the mucosa-associated lymphoid immune tissue, these TJ-protein-targeted strategies may also provide platforms for the development of novel therapies and vaccines. Here, this paper reviews two TJ-protein-targeted technologies, claudin binders and an angulin binder, and their applications in drug development. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

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17 pages, 1359 KiB

Open AccessReview

Role of Tricellular Tight Junction Protein Lipolysis-Stimulated Lipoprotein Receptor (LSR) in Cancer Cells

by Takayuki Kohno, Takumi Konno and Takashi Kojima

Int. J. Mol. Sci. 2019, 20(14), 3555; https://doi.org/10.3390/ijms20143555 - 20 Jul 2019

Cited by 21 | Viewed by 5934

Abstract

Maintaining a robust epithelial barrier requires the accumulation of tight junction proteins, LSR/angulin-1 and tricellulin, at the tricellular contacts. Alterations in the localization of these proteins temporarily cause epithelial barrier dysfunction, which is closely associated with not only physiological differentiation but also cancer [...] Read more.

Maintaining a robust epithelial barrier requires the accumulation of tight junction proteins, LSR/angulin-1 and tricellulin, at the tricellular contacts. Alterations in the localization of these proteins temporarily cause epithelial barrier dysfunction, which is closely associated with not only physiological differentiation but also cancer progression and metastasis. In normal human endometrial tissues, the endometrial cells undergo repeated proliferation and differentiation under physiological conditions. Recent observations have revealed that the localization and expression of LSR/angulin-1 and tricellulin are altered in a menstrual cycle-dependent manner. Moreover, it has been shown that endometrial cancer progression affects these alterations. This review highlights the differences in the localization and expression of tight junction proteins in normal endometrial cells and endometrial cancers and how they cause functional changes in cells. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

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23 pages, 3278 KiB

Open AccessReview

Regulation of Epithelial Cell Functions by the Osmolality and Hydrostatic Pressure Gradients: A Possible Role of the Tight Junction as a Sensor

by Shinsaku Tokuda and Alan S. L. Yu

Int. J. Mol. Sci. 2019, 20(14), 3513; https://doi.org/10.3390/ijms20143513 - 17 Jul 2019

Cited by 18 | Viewed by 5113

Abstract

Epithelia act as a barrier to the external environment. The extracellular environment constantly changes, and the epithelia are required to regulate their function in accordance with the changes in the environment. It has been reported that a difference of the environment between the [...] Read more.

Epithelia act as a barrier to the external environment. The extracellular environment constantly changes, and the epithelia are required to regulate their function in accordance with the changes in the environment. It has been reported that a difference of the environment between the apical and basal sides of epithelia such as osmolality and hydrostatic pressure affects various epithelial functions including transepithelial transport, cytoskeleton, and cell proliferation. In this paper, we review the regulation of epithelial functions by the gradients of osmolality and hydrostatic pressure. We also examine the significance of this regulation in pathological conditions especially focusing on the role of the hydrostatic pressure gradient in the pathogenesis of carcinomas. Furthermore, we discuss the mechanism by which epithelia sense the osmotic and hydrostatic pressure gradients and the possible role of the tight junction as a sensor of the extracellular environment to regulate epithelial functions. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)

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