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Function of Transglutaminases in Adhesion Dynamics, Differentiation, and Cell Survival

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Biophysics".

Deadline for manuscript submissions: closed (15 March 2022) | Viewed by 41841

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Prof. Dr. Elisabetta Verderio Edwards

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Centre for Health, Ageing and Understanding Disease (CHAUD), School of Science and Technology, Nottingham Trent University, Nottingham, NG118NS, UK and Department of Biological, Geological, Environmental Sciences (BIGEA), University of Bologna, 40126 Bologna, Italy
Interests: transglutaminases; extracellular matrix; wound healing and fibrosis; chronic kidney disease

Prof. Dr. Mari T. Kaartinen

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Faculty of Medicine (Division of Experimental Medicine) and Faculty of Dentistry, McGill University, Montreal, QC H3A 0C7, Canada
Interests: transglutaminases; extracellular matrix; bone remodeling; adipogenesis; osteoporosis; energy metabilism

Dr. Anne-Marie van Dam

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Amsterdam UMC, Vrije Universiteit Amsterdam, Dept. Anatomy and Neurosciences, Amsterdam Neuroscience, 1081 HZ Amsterdam, The Netherlands
Interests: glial cells; transglutaminases; inflammation; neurodegenerative diseases; cell adhesion and migration

Special Issue Information

Dear Colleagues,

Cells Special Issue on ‘Transglutaminase 2 (TG2) in Cell Adhesion Dynamics, Cell Differentiation and Cell Survival’

TG2 is a widely expressed transglutaminase whose expression and activity is associated with various human diseases, including coeliac disease, chronic lung and kidney diseases, and neurological disorders, such as multiple sclerosis. The enzyme TG2 mediates its actions via multiple activities and mechanisms, which depend on its molecular conformation, cellular redox-state, and presence of GTP and/or Ca²⁺. TG2 crosslinks intra- and extracellular proteins, acts as a GTPase and GTP-binding signaling protein, and mediates cell–matrix adhesion via its fibronectin-binding domain. As a consequence, TG2 has been shown to be involved in cell differentiation, migration, and survival.

Many novel compounds have been developed to modulate the conformation and activity of TG2, thereby opening avenues for therapeutic interventions. Promising initiatives are under way for coeliac disease and tissue fibrosis.

With this Special Issue, we hope to collect original research, reviews, communications or concept papers that give insights into the advances that have been made in understanding mechanisms of action of TG2 in cell adhesion, differentiation, and survival. We hope to highlight TG2 in disease processes as well as assemble current knowledge and translational prospects of TG2 research.

Prof. Dr. Elisabetta Verderio Edwards
Prof. Dr. Mari T. Kaartinen
Dr. Anne-Marie van Dam
Guest Editors

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Keywords

Tissue transglutaminase
Disease
Fibrosis
Mechanism of action
Cell adhesion/migration
Cell survival
Cell death
TG2 inhibition
Translational studies

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Published Papers (9 papers)

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Research

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15 pages, 28143 KiB

Open AccessArticle

Increased Osteoclastogenesis in Absence of TG2 Is Reversed by Transglutaminase Inhibition—Evidence for the Role for TG1 in Osteoclast Formation

by Sahar Ebrahimi Samani and Mari T. Kaartinen

Cells 2023, 12(17), 2139; https://doi.org/10.3390/cells12172139 - 24 Aug 2023

Cited by 1 | Viewed by 1657

Abstract

Osteoclasts are multinucleated, bone-resorbing giant cells derived from monocyte–macrophage cell lines. Increased bone resorption results in loss of bone mass and osteoporosis. Osteoclast and bone marrow macrophages have been shown to express three TG enzymes (TG2, Factor XIII-A, and TG1) and TG activity to regulate osteoclast differentiation from bone marrow macrophages in vitro. In vivo and in vitro studies have demonstrated that the deletion of TG2 causes increased osteoclastogenesis and a significant loss of bone mass in mice (Tgm2−/− mice). Here, we confirm that TG2 deficiency results in increased osteoclastogenesis in vitro and show that this increase can be reversed by a TG inhibitor, NC9, suggesting that other TGs are responsible for driving osteoclastogenesis in the absence of TG2. An assessment of total TG activity with 5-(biotinamido)-pentylamine, as well as TG1 and FXIII-A activities using TG-specific Hitomi peptides (bK5 and bF11) in Tgm2−/− bone marrow flushes, bone marrow macrophages, and osteoclasts, showed a significant increase in total TG activity and TG1 activity. Factor XIII-A activity was unchanged. Aspartate proteases, such as cathepsins, are involved in the degradation of organic bone matrix and can be produced by osteoclasts. Moreover, Cathepsin D was shown in previous work to be increased in TG2-null cells and is known to activate TG1. We show that Pepstatin A, an aspartate protease inhibitor, blocks osteoclastogenesis in wild-type and Tgm2−/− cells and decreases TG1 activity in Tgm2−/− osteoclasts. Cathepsin D protein levels were unaltered in Tgm2−/−cells and its activity moderately but significantly increased. Tgm2−/− and Tgm2+/+ bone marrow macrophages and osteoclasts also expressed Cathepsin E, and Renin of the aspartate protease family, suggesting their potential involvement in this process. Our study brings further support to the observation that TGs are significant regulators of osteoclastogenesis and that the absence of TG2 can cause increased activity of other TGs, such as TG1. Full article

(This article belongs to the Special Issue Function of Transglutaminases in Adhesion Dynamics, Differentiation, and Cell Survival)

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27 pages, 3931 KiB

Open AccessArticle

The Transglutaminase-2 Interactome in the APP23 Mouse Model of Alzheimer’s Disease

by Micha M. M. Wilhelmus, Elisa Tonoli, Clare Coveney, David J. Boocock, Cornelis A. M. Jongenelen, John J. P. Brevé, Elisabetta A. M. Verderio and Benjamin Drukarch

Cells 2022, 11(3), 389; https://doi.org/10.3390/cells11030389 - 24 Jan 2022

Cited by 7 | Viewed by 3600

Abstract

Amyloid-beta (Aβ) deposition in the brain is closely linked with the development of Alzheimer’s disease (AD). Unfortunately, therapies specifically targeting Aβ deposition have failed to reach their primary clinical endpoints, emphasizing the need to broaden the search strategy for alternative targets/mechanisms. Transglutaminase-2 (TG2) catalyzes post-translational modifications, is present in AD lesions and interacts with AD-associated proteins. However, an unbiased overview of TG2 interactors is lacking in both control and AD brain. Here we aimed to identify these interactors using a crossbreed of the AD-mimicking APP23 mouse model with wild type and TG2 knock-out (TG2^−/−) mice. We found that absence of TG2 had no (statistically) significant effect on Aβ pathology, soluble brain levels of Aβ_1–40 and Aβ_1–42, and mRNA levels of TG family members compared to APP23 mice at 18 months of age. Quantitative proteomics and network analysis revealed a large cluster of TG2 interactors involved in synaptic transmission/assembly and cell adhesion in the APP23 brain typical of AD. Comparative proteomics of wild type and TG2^−/− brains revealed a TG2-linked pathological proteome consistent with alterations in both pathways. Our data show that TG2 deletion leads to considerable network alterations consistent with a TG2 role in (dys)regulation of synaptic transmission and cell adhesion in APP23 brains. Full article

(This article belongs to the Special Issue Function of Transglutaminases in Adhesion Dynamics, Differentiation, and Cell Survival)

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21 pages, 4486 KiB

Open AccessArticle

Impaired Skeletal Muscle Development and Regeneration in Transglutaminase 2 Knockout Mice

by Zsófia Budai, Nour Al-Zaeed, Péter Szentesi, Hajnalka Halász, László Csernoch, Zsuzsa Szondy and Zsolt Sarang

Cells 2021, 10(11), 3089; https://doi.org/10.3390/cells10113089 - 9 Nov 2021

Cited by 11 | Viewed by 3307

Abstract

Skeletal muscle regeneration is triggered by local inflammation and is accompanied by phagocytosis of dead cells at the injury site. Efferocytosis regulates the inflammatory program in macrophages by initiating the conversion of their inflammatory phenotype into the healing one. While pro-inflammatory cytokines induce satellite cell proliferation and differentiation into myoblasts, growth factors, such as GDF3, released by healing macrophages drive myoblast fusion and myotube growth. Therefore, improper efferocytosis may lead to impaired muscle regeneration. Transglutaminase 2 (TG2) is a versatile enzyme participating in efferocytosis. Here, we show that TG2 ablation did not alter the skeletal muscle weights or sizes but led to the generation of small size myofibers and to decreased grip force in TG2 null mice. Following cardiotoxin-induced injury, the size of regenerating fibers was smaller, and the myoblast fusion was delayed in the tibialis anterior muscle of TG2 null mice. Loss of TG2 did not affect the efferocytic capacity of muscle macrophages but delayed their conversion to Ly6C⁻CD206⁺, GDF3 expressing cells. Finally, TG2 promoted myoblast fusion in differentiating C2C12 myoblasts. These results indicate that TG2 expressed by both macrophages and myoblasts contributes to proper myoblast fusion, and its ablation leads to impaired muscle development and regeneration in mice. Full article

(This article belongs to the Special Issue Function of Transglutaminases in Adhesion Dynamics, Differentiation, and Cell Survival)

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19 pages, 3676 KiB

Open AccessArticle

The Motility and Mesenchymal Features of Breast Cancer Cells Correlate with the Levels and Intracellular Localization of Transglutaminase Type 2

by Nicoletta Bianchi, Federica Brugnoli, Silvia Grassilli, Karine Bourgeois, Jeffrey W. Keillor, Carlo M. Bergamini, Gianluca Aguiari, Stefano Volinia and Valeria Bertagnolo

Cells 2021, 10(11), 3059; https://doi.org/10.3390/cells10113059 - 6 Nov 2021

Cited by 10 | Viewed by 2546

Abstract

We have investigated motility in breast cancer cell lines in association with the expression of Transglutaminase type 2 (TG2) as well as upon the administration of Doxorubicin (Dox), an active cytotoxic agent that is employed in chemotherapy. The exposure of MCF-7 cells to the drug increased TG2 levels, triggering epithelial–mesenchymal transition (EMT), thereby supporting cell motility. The effects of Dox on the movement of MCF-7 cells were counteracted by treatment with NC9, a TG2 inhibitor, which induced morphological changes and also reduced the migration of MDA-MB-231 cells exhibiting high levels of TG2. The physical association of TG2 with the cytoskeletal component vimentin appeared pivotal both in drug-treated MCF-7 and in MDA-MB-231 cells and seemed to be independent of the catalytic activity of TG2. NC9 altered the subcellular distribution of TG2 and, consequently, the co-localization of TG2 with vimentin. Furthermore, NC9 induced a nuclear accumulation of TG2 as a prelude to TG2-dependent gene expression modifications. Since enzyme activity can affect both motility and nuclear functions, targeting of this protein could represent a method to improve therapeutic interventions in breast tumors, particularly those to control progression and to limit drug resistance. Full article

(This article belongs to the Special Issue Function of Transglutaminases in Adhesion Dynamics, Differentiation, and Cell Survival)

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15 pages, 4802 KiB

Open AccessArticle

Deletion or Inhibition of Astrocytic Transglutaminase 2 Promotes Functional Recovery after Spinal Cord Injury

by Anissa Elahi, Jacen Emerson, Jacob Rudlong, Jeffrey W. Keillor, Garrick Salois, Adam Visca, Peter Girardi, Gail V.W. Johnson and Christoph Pröschel

Cells 2021, 10(11), 2942; https://doi.org/10.3390/cells10112942 - 29 Oct 2021

Cited by 10 | Viewed by 2901

Abstract

Following CNS injury, astrocytes become “reactive” and exhibit pro-regenerative or harmful properties. However, the molecular mechanisms that cause astrocytes to adopt either phenotype are not well understood. Transglutaminase 2 (TG2) plays a key role in regulating the response of astrocytes to insults. Here, we used mice in which TG2 was specifically deleted in astrocytes (Gfap-Cre+/− TG2fl/fl, referred to here as TG2-A-cKO) in a spinal cord contusion injury (SCI) model. Deletion of TG2 from astrocytes resulted in a significant improvement in motor function following SCI. GFAP and NG2 immunoreactivity, as well as number of SOX9 positive cells, were significantly reduced in TG2-A-cKO mice. RNA-seq analysis of spinal cords from TG2-A-cKO and control mice 3 days post-injury identified thirty-seven differentially expressed genes, all of which were increased in TG2-A-cKO mice. Pathway analysis revealed a prevalence for fatty acid metabolism, lipid storage and energy pathways, which play essential roles in neuron–astrocyte metabolic coupling. Excitingly, treatment of wild type mice with the selective TG2 inhibitor VA4 significantly improved functional recovery after SCI, similar to what was observed using the genetic model. These findings indicate the use of TG2 inhibitors as a novel strategy for the treatment of SCI and other CNS injuries. Full article

(This article belongs to the Special Issue Function of Transglutaminases in Adhesion Dynamics, Differentiation, and Cell Survival)

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Review

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24 pages, 1416 KiB

Open AccessReview

The Outside-In Journey of Tissue Transglutaminase in Cancer

by Livia Elena Sima, Daniela Matei and Salvatore Condello

Cells 2022, 11(11), 1779; https://doi.org/10.3390/cells11111779 - 29 May 2022

Cited by 12 | Viewed by 3479

Abstract

Tissue transglutaminase (TG2) is a member of the transglutaminase family that catalyzes Ca²⁺-dependent protein crosslinks and hydrolyzes guanosine 5′-triphosphate (GTP). The conformation and functions of TG2 are regulated by Ca²⁺ and GTP levels; the TG2 enzymatically active open conformation is modulated by high Ca²⁺ concentrations, while high intracellular GTP promotes the closed conformation, with inhibition of the TG-ase activity. TG2’s unique characteristics and its ubiquitous distribution in the intracellular compartment, coupled with its secretion in the extracellular matrix, contribute to modulate the functions of the protein. Its aberrant expression has been observed in several cancer types where it was linked to metastatic progression, resistance to chemotherapy, stemness, and worse clinical outcomes. The N-terminal domain of TG2 binds to the 42 kDa gelatin-binding domain of fibronectin with high affinity, facilitating the formation of a complex with β-integrins, essential for cellular adhesion to the matrix. This mechanism allows TG2 to interact with key matrix proteins and to regulate epithelial to mesenchymal transition and stemness. Here, we highlight the current knowledge on TG2 involvement in cancer, focusing on its roles translating extracellular cues into activation of oncogenic programs. Improved understanding of these mechanisms could lead to new therapeutic strategies targeting this multi-functional protein. Full article

(This article belongs to the Special Issue Function of Transglutaminases in Adhesion Dynamics, Differentiation, and Cell Survival)

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17 pages, 2784 KiB

Open AccessReview

Plant Transglutaminases: New Insights in Biochemistry, Genetics, and Physiology

by Luigi Parrotta, Umesh Kumar Tanwar, Iris Aloisi, Ewa Sobieszczuk-Nowicka, Magdalena Arasimowicz-Jelonek and Stefano Del Duca

Cells 2022, 11(9), 1529; https://doi.org/10.3390/cells11091529 - 3 May 2022

Cited by 9 | Viewed by 3185

Abstract

Transglutaminases (TGases) are calcium-dependent enzymes that catalyse an acyl-transfer reaction between primary amino groups and protein-bound Gln residues. They are widely distributed in nature, being found in vertebrates, invertebrates, microorganisms, and plants. TGases and their functionality have been less studied in plants than humans and animals. TGases are distributed in all plant organs, such as leaves, tubers, roots, flowers, buds, pollen, and various cell compartments, including chloroplasts, the cytoplasm, and the cell wall. Recent molecular, physiological, and biochemical evidence pointing to the role of TGases in plant biology and the mechanisms in which they are involved allows us to consider their role in processes such as photosynthesis, plant fertilisation, responses to biotic and abiotic stresses, and leaf senescence. In the present paper, an in-depth description of the biochemical characteristics and a bioinformatics comparison of plant TGases is provided. We also present the phylogenetic relationship, gene structure, and sequence alignment of TGase proteins in various plant species, not described elsewhere. Currently, our knowledge of these proteins in plants is still insufficient. Further research with the aim of identifying and describing the regulatory components of these enzymes and the processes regulated by them is needed. Full article

(This article belongs to the Special Issue Function of Transglutaminases in Adhesion Dynamics, Differentiation, and Cell Survival)

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18 pages, 2911 KiB

Open AccessReview

Role of Transglutaminase 2 in Cell Death, Survival, and Fibrosis

by Hideki Tatsukawa and Kiyotaka Hitomi

Cells 2021, 10(7), 1842; https://doi.org/10.3390/cells10071842 - 20 Jul 2021

Cited by 48 | Viewed by 9122

Abstract

Transglutaminase 2 (TG2) is a ubiquitously expressed enzyme catalyzing the crosslinking between Gln and Lys residues and involved in various pathophysiological events. Besides this crosslinking activity, TG2 functions as a deamidase, GTPase, isopeptidase, adapter/scaffold, protein disulfide isomerase, and kinase. It also plays a role in the regulation of hypusination and serotonylation. Through these activities, TG2 is involved in cell growth, differentiation, cell death, inflammation, tissue repair, and fibrosis. Depending on the cell type and stimulus, TG2 changes its subcellular localization and biological activity, leading to cell death or survival. In normal unstressed cells, intracellular TG2 exhibits a GTP-bound closed conformation, exerting prosurvival functions. However, upon cell stimulation with Ca²⁺ or other factors, TG2 adopts a Ca²⁺-bound open conformation, demonstrating a transamidase activity involved in cell death or survival. These functional discrepancies of TG2 open form might be caused by its multifunctional nature, the existence of splicing variants, the cell type and stimulus, and the genetic backgrounds and variations of the mouse models used. TG2 is also involved in the phagocytosis of dead cells by macrophages and in fibrosis during tissue repair. Here, we summarize and discuss the multifunctional and controversial roles of TG2, focusing on cell death/survival and fibrosis. Full article

(This article belongs to the Special Issue Function of Transglutaminases in Adhesion Dynamics, Differentiation, and Cell Survival)

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Other

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20 pages, 1304 KiB

Open AccessPerspective

Features of ZED1227: The First-In-Class Tissue Transglutaminase Inhibitor Undergoing Clinical Evaluation for the Treatment of Celiac Disease

by Christian Büchold, Martin Hils, Uwe Gerlach, Johannes Weber, Christiane Pelzer, Andreas Heil, Daniel Aeschlimann and Ralf Pasternack

Cells 2022, 11(10), 1667; https://doi.org/10.3390/cells11101667 - 17 May 2022

Cited by 29 | Viewed by 9997

Abstract

ZED1227 is a small molecule tissue transglutaminase (TG2) inhibitor. The compound selectively binds to the active state of TG2, forming a stable covalent bond with the cysteine in its catalytic center. The molecule was designed for the treatment of celiac disease. Celiac disease is an autoimmune-mediated chronic inflammatory condition of the small intestine affecting about 1–2% of people in Caucasian populations. The autoimmune disease is triggered by dietary gluten. Consumption of staple foods containing wheat, barley, or rye leads to destruction of the small intestinal mucosa in genetically susceptible individuals, and this is accompanied by the generation of characteristic TG2 autoantibodies. TG2 plays a causative role in the pathogenesis of celiac disease. Upon activation by Ca²⁺, it catalyzes the deamidation of gliadin peptides as well as the crosslinking of gliadin peptides to TG2 itself. These modified biological structures trigger breaking of oral tolerance to gluten, self-tolerance to TG2, and the activation of cytotoxic immune cells in the gut mucosa. Recently, in an exploratory proof-of-concept study, ZED1227 administration clinically validated TG2 as a “druggable” target in celiac disease. Here, we describe the specific features and profiling data of the drug candidate ZED1227. Further, we give an outlook on TG2 inhibition as a therapeutic approach in indications beyond celiac disease. Full article

(This article belongs to the Special Issue Function of Transglutaminases in Adhesion Dynamics, Differentiation, and Cell Survival)

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