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Transglutaminase Diseases, from the Experimental Laboratory to Human Pathology Applications
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Transglutaminase Diseases, from the Experimental Laboratory to Human Pathology Applications

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 June 2020) | Viewed by 19781

Special Issue Editors

Prof. Dr. Simone Beninati

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Guest Editor
Department of Biology, University of Tor Vergata, Rome, Italy
Interests: experimental oncology; biochemistry
Special Issues, Collections and Topics in MDPI journals
Dr. Carlo Mischiati

E-Mail Website
Guest Editor
Clinical Biochemistry Laboratory, Department of Neurosciences and Rehabilitation, Faculty of Medicine, Pharmacy and Prevention, University of Ferrara, Via Luigi Borsari 46, Ferrara, Italy
Interests: biochemistry; molecular biology; medical genetics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Transglutaminases are ubiquitous enzymes which catalyze posttranslational modifications of proteins. Recently, transglutaminase-catalyzed posttranslational modification of proteins has been shown to be involved in the molecular mechanisms responsible for human diseases. This family of enzymes has been associated with inflammation, cancer, fibrosis, cardiovascular disease, and celiac disease, in which it plays either a protective role or contributes to the pathogenesis. Transglutaminase activity has been hypothesized to also be involved in the pathogenetic mechanisms responsible for several human neurodegenerative diseases. Alzheimer’s disease and other neurodegenerative diseases, such as Parkinson’s disease, supranuclear palsy, Huntington’s disease, and other polyglutamine diseases, are characterized in part by aberrant cerebral transglutaminase activity and by increased cross-linked proteins in affected brains.

We are pleased to invite you to contribute to the Special Issue, “Transglutaminase Diseases, from the Experimental Laboratory to Human Pathology Applications", which will be published in the International Journal of Molecular Sciences (IF 3.7), an international peer-reviewed open access journal providing an advanced forum for biochemistry, molecular and cell biology, and molecular biophysics, published semi-monthly online by MDPI. Citations are available in PubMed, and full texts are archived in PubMed Central. The objective of this Special Issue is to collect and publish both experimental and theoretical contributions from original and high-quality research articles and to encourage researchers to investigate topics in the field of transglutaminases in various diseases.

Prof. Dr. Simone Beninati
Dr. Carlo Mischiati
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Published Papers (6 papers)

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Research

12 pages, 1823 KiB  
Article
Polyamine Oxidase Is Involved in Spermidine Reduction of Transglutaminase Type 2-Catalyzed βH-Crystallins Polymerization in Calcium-Induced Experimental Cataract
by Carlo Mischiati, Giordana Feriotto, Claudio Tabolacci, Fabio Domenici, Sonia Melino, Ilaria Borromeo, Cinzia Forni, Angelo De Martino and Simone Beninati
Int. J. Mol. Sci. 2020, 21(15), 5427; https://doi.org/10.3390/ijms21155427 - 30 Jul 2020
Cited by 5 | Viewed by 2328
Abstract
In an in vitro Ca2+-induced cataract model, the progression of opacification is paralleled by a rapid decrease of the endogenous levels of spermidine (SPD) and an increase of transglutaminase type 2 (TG2, EC 2.3.2.13)-catalyzed lens crystallins cross-linking by protein-bound N1 [...] Read more.
In an in vitro Ca2+-induced cataract model, the progression of opacification is paralleled by a rapid decrease of the endogenous levels of spermidine (SPD) and an increase of transglutaminase type 2 (TG2, EC 2.3.2.13)-catalyzed lens crystallins cross-linking by protein-bound N1-N8-bis(γ-glutamyl) SPD. This pattern was reversed adding exogenous SPD to the incubation resulting in a delayed loss of transparency of the rabbit lens. The present report shows evidence on the main incorporation of SPD by the catalytic activity of TG2, toward βH-crystallins and in particular to the βB2- and mostly in βB3-crystallins. The increase of endogenous SPD in the cultured rabbit lens showed the activation of a flavin adenine dinucleotide (FAD)-dependent polyamine oxidases (PAO EC 1.5.3.11). As it is known that FAD-PAO degrades the N8-terminal reactive portion of N1-mono(γ-glutamyl) SPD, the protein-bound N8-mono(γ-glutamyl) SPD was found the mainly available derivative for the potential formation of βB3-crystallins cross-links by protein-bound N1-N8-bis(γ-glutamyl)SPD. In conclusion, FAD-PAO degradation of the N8-terminal reactive residue of the crystallins bound N1-mono(γ-glutamyl)SPD together with the increased concentration of exogenous SPD, leading to saturation of glutamine residues on the substrate proteins, drastically reduces N1-N8-bis(γ-glutamyl)SPD crosslinks formation, preventing crystallins polymerization and avoiding rabbit lens opacification. The ability of SPD and MDL 72527 to modulate the activities of TG2 and FAD-PAO involved in the mechanism of lens opacification suggests a potential strategy for the prevention of senile cataract. Full article
(This article belongs to the Special Issue Transglutaminase Diseases, from the Experimental Laboratory to Human Pathology Applications)
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13 pages, 2176 KiB  
Article
Transglutaminase 2-Mediated p53 Depletion Promotes Angiogenesis by Increasing HIF-1α-p300 Binding in Renal Cell Carcinoma
by Seon-Hyeong Lee, Joon Hee Kang, Ji Sun Ha, Jae-Seon Lee, Su-Jin Oh, Hyun-Jung Choi, Jaewhan Song and Soo-Youl Kim
Int. J. Mol. Sci. 2020, 21(14), 5042; https://doi.org/10.3390/ijms21145042 - 17 Jul 2020
Cited by 18 | Viewed by 3425
Abstract
Angiogenesis and the expression of vascular endothelial growth factor (VEGF) are increased in renal cell carcinoma (RCC). Transglutaminase 2 (TGase 2), which promotes angiogenesis in endothelial cells during wound healing, is upregulated in RCC. Tumor angiogenesis involves three domains: cancer cells, the extracellular [...] Read more.
Angiogenesis and the expression of vascular endothelial growth factor (VEGF) are increased in renal cell carcinoma (RCC). Transglutaminase 2 (TGase 2), which promotes angiogenesis in endothelial cells during wound healing, is upregulated in RCC. Tumor angiogenesis involves three domains: cancer cells, the extracellular matrix, and endothelial cells. TGase 2 stabilizes VEGF in the extracellular matrix and promotes VEGFR-2 nuclear translocation in endothelial cells. However, the role of TGase 2 in angiogenesis in the cancer cell domain remains unclear. Hypoxia-inducible factor (HIF)-1α-mediated VEGF production underlies the induction of angiogenesis in cancer cells. In this study, we show that p53 downregulated HIF-1α in RCC, and p53 overexpression decreased VEGF production. Increased TGase 2 promoted angiogenesis by inducing p53 degradation, leading to the activation of HIF-1α. The interaction of HIF-1α and p53 with the cofactor p300 is required for stable transcriptional activation. We found that TGase 2-mediated p53 depletion increased the availability of p300 for HIF-1α-p300 binding. A preclinical xenograft model suggested that TGase 2 inhibition can reverse angiogenesis in RCC. Full article
(This article belongs to the Special Issue Transglutaminase Diseases, from the Experimental Laboratory to Human Pathology Applications)
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18 pages, 2391 KiB  
Article
Transglutaminase 2 Has Metabolic and Vascular Regulatory Functions Revealed by In Vivo Activation of Alpha1-Adrenergic Receptor
by Kinga Lénárt, Attila Pap, Róbert Pórszász, Anna V. Oláh, László Fésüs and András Mádi
Int. J. Mol. Sci. 2020, 21(11), 3865; https://doi.org/10.3390/ijms21113865 - 29 May 2020
Cited by 3 | Viewed by 3102
Abstract
The multifunctional tissue transglutaminase has been demonstrated to act as α1-adrenergic receptor-coupled G protein with GTPase activity in several cell types. To explore further the pathophysiological significance of this function we investigated the in vivo effects of the α1-adrenergic receptor agonist phenylephrine comparing [...] Read more.
The multifunctional tissue transglutaminase has been demonstrated to act as α1-adrenergic receptor-coupled G protein with GTPase activity in several cell types. To explore further the pathophysiological significance of this function we investigated the in vivo effects of the α1-adrenergic receptor agonist phenylephrine comparing responses in wild type and TG2-/- mice. Injection of phenylephrine, but not a beta3-adrenergic agonist (CL-316,243), resulted in the long-term decline of the respiratory exchange ratio and lower lactate concentration in TG2-/- mice indicating they preferred to utilize fatty acids instead of glucose as fuels. Measurement of tail blood pressure revealed that the vasoconstrictive effect of phenylephrine was milder in TG2-/- mice leading to lower levels of lactate dehydrogenase (LDH) isoenzymes in blood. LDH isoenzyme patterns indicated more damage in lung, liver, kidney, skeletal, and cardiac muscle of wild type mice; the latter was confirmed by a higher level of heart-specific CK-MB. Our data suggest that TG2 as an α1-adrenergic receptor-coupled G protein has important regulatory functions in alpha1-adrenergic receptor-mediated metabolic processes and vascular functions. Full article
(This article belongs to the Special Issue Transglutaminase Diseases, from the Experimental Laboratory to Human Pathology Applications)
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11 pages, 2303 KiB  
Communication
Transglutaminase 3 Reduces the Severity of Psoriasis in Imiquimod-Treated Mouse Skin
by Maria Cristina Piro, Alessandra Ventura, Artem Smirnov, Andrea Saggini, Anna Maria Lena, Alessandro Mauriello, Luca Bianchi, Gerry Melino and Eleonora Candi
Int. J. Mol. Sci. 2020, 21(5), 1566; https://doi.org/10.3390/ijms21051566 - 25 Feb 2020
Cited by 11 | Viewed by 3175
Abstract
Four transglutaminase (TG) isoforms have been detected in epidermal keratinocytes: TG1, TG2, TG3, and TG5. Except for TG1 and TG3, their contribution to keratinocyte development and structure remains undefined. In this paper, we focused on the roles of TG2 and TG3 in imiquimod-induced [...] Read more.
Four transglutaminase (TG) isoforms have been detected in epidermal keratinocytes: TG1, TG2, TG3, and TG5. Except for TG1 and TG3, their contribution to keratinocyte development and structure remains undefined. In this paper, we focused on the roles of TG2 and TG3 in imiquimod-induced psoriasis in mouse skin. We evaluated the severity of psoriasis markers in the skin of imiquimod-treated TG3 null and TG2 null mice. Our results showed that compromised TG3KO mouse skin was more responsive than WT or TG2KO mouse skin to the action of the pro-inflammatory drug imiquimod. Full article
(This article belongs to the Special Issue Transglutaminase Diseases, from the Experimental Laboratory to Human Pathology Applications)
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13 pages, 2451 KiB  
Article
Hypoxia-Dependent Expression of TG2 Isoforms in Neuroblastoma Cells as Consequence of Different MYCN Amplification Status
by Monica Currò, Nadia Ferlazzo, Maria Laura Giunta, Angela Simona Montalto, Tiziana Russo, Salvatore Arena, Pietro Impellizzeri, Daniela Caccamo, Carmelo Romeo and Riccardo Ientile
Int. J. Mol. Sci. 2020, 21(4), 1364; https://doi.org/10.3390/ijms21041364 - 18 Feb 2020
Cited by 6 | Viewed by 3047
Abstract
Transglutaminase 2 (TG2) is a multifunctional enzyme and two isoforms, TG2-L and TG2-S, exerting opposite effects in the regulation of cell death and survival, have been revealed in cancer tissues. Notably, in cancer cells a hypoxic environment may stimulate tumor growth, invasion and [...] Read more.
Transglutaminase 2 (TG2) is a multifunctional enzyme and two isoforms, TG2-L and TG2-S, exerting opposite effects in the regulation of cell death and survival, have been revealed in cancer tissues. Notably, in cancer cells a hypoxic environment may stimulate tumor growth, invasion and metastasis. Here we aimed to characterize the role of TG2 isoforms in neuroblastoma cell fate under hypoxic conditions. The mRNA levels of TG2 isoforms, hypoxia-inducible factor (HIF)-1α, p16, cyclin D1 and B1, as well as markers of cell proliferation/death, DNA damage, and cell cycle were examined in SH-SY5Y (non-MYCN-amplified) and IMR-32 (MYCN-amplified) neuroblastoma cells in hypoxia/reoxygenation conditions. The exposure to hypoxia induced the up-regulation of HIF-1α in both cell lines. Hypoxic conditions caused the up-regulation of TG2-S and the reduction of cell viability/proliferation associated with DNA damage in SH-SY5Y cells, while in IMR-32 did not produce DNA damage, and increased the levels of both TG2 isoforms and proliferation markers. Different cell response to hypoxia can be mediated by TG2 isoforms in function of MYCN amplification status. A better understanding of the role of TG2 isoforms in neuroblastoma may open new venues in a diagnostic and therapeutic perspective. Full article
(This article belongs to the Special Issue Transglutaminase Diseases, from the Experimental Laboratory to Human Pathology Applications)
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16 pages, 5183 KiB  
Article
Competitive Binding of Magnesium to Calcium Binding Sites Reciprocally Regulates Transamidase and GTP Hydrolysis Activity of Transglutaminase 2
by Eui Man Jeong, Ki Baek Lee, Gi Eob Kim, Chang Min Kim, Jin-Haeng Lee, Hyo-Jun Kim, Ji-Woong Shin, Mee-ae Kwon, Hyun Ho Park and In-Gyu Kim
Int. J. Mol. Sci. 2020, 21(3), 791; https://doi.org/10.3390/ijms21030791 - 25 Jan 2020
Cited by 13 | Viewed by 4002
Abstract
Transglutaminase 2 (TG2) is a Ca2+-dependent enzyme, which regulates various cellular processes by catalyzing protein crosslinking or polyamination. Intracellular TG2 is activated and inhibited by Ca2+ and GTP binding, respectively. Although aberrant TG2 activation has been implicated in the pathogenesis [...] Read more.
Transglutaminase 2 (TG2) is a Ca2+-dependent enzyme, which regulates various cellular processes by catalyzing protein crosslinking or polyamination. Intracellular TG2 is activated and inhibited by Ca2+ and GTP binding, respectively. Although aberrant TG2 activation has been implicated in the pathogenesis of diverse diseases, including cancer and degenerative and fibrotic diseases, the structural basis for the regulation of TG2 by Ca2+ and GTP binding is not fully understood. Here, we produced and analyzed a Ca2+-containing TG2 crystal, and identified two glutamate residues, E437 and E539, as Ca2+-binding sites. The enzymatic analysis of the mutants revealed that Ca2+ binding to these sites is required for the transamidase activity of TG2. Interestingly, we found that magnesium (Mg2+) competitively binds to the E437 and E539 residues. The Mg2+ binding to these allosteric sites enhances the GTP binding/hydrolysis activity but inhibits transamidase activity. Furthermore, HEK293 cells transfected with mutant TG2 exhibited higher transamidase activity than cells with wild-type TG2. Cells with wild-type TG2 showed an increase in transamidase activity under Mg2+-depleted conditions, whereas cells with mutant TG2 were unaffected. These results indicate that E437 and E539 are Ca2+-binding sites contributing to the reciprocal regulation of transamidase and GTP binding/hydrolysis activities of TG2 through competitive Mg2+ binding. Full article
(This article belongs to the Special Issue Transglutaminase Diseases, from the Experimental Laboratory to Human Pathology Applications)
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