Special Issue "Function of Transglutaminases in Adhesion Dynamics, Differentiation, and Cell Survival"

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

Deadline for manuscript submissions: 15 March 2022.

Special Issue Editors

Prof. Dr. Elisabetta Verderio Edwards
E-Mail Website
Guest Editor
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
E-Mail Website
Guest Editor
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
E-Mail
Guest Editor
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

Manuscript Submission Information

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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. Cells is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2000 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

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

Published Papers (4 papers)

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Research

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Article
Impaired Skeletal Muscle Development and Regeneration in Transglutaminase 2 Knockout Mice
Cells 2021, 10(11), 3089; https://doi.org/10.3390/cells10113089 - 09 Nov 2021
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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 [...] Read more.
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 Ly6CCD206+, 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
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Article
The Motility and Mesenchymal Features of Breast Cancer Cells Correlate with the Levels and Intracellular Localization of Transglutaminase Type 2
Cells 2021, 10(11), 3059; https://doi.org/10.3390/cells10113059 - 06 Nov 2021
Viewed by 270
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 [...] Read more.
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
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Article
Deletion or Inhibition of Astrocytic Transglutaminase 2 Promotes Functional Recovery after Spinal Cord Injury
Cells 2021, 10(11), 2942; https://doi.org/10.3390/cells10112942 - 29 Oct 2021
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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, [...] Read more.
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
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Review

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Review
Role of Transglutaminase 2 in Cell Death, Survival, and Fibrosis
Cells 2021, 10(7), 1842; https://doi.org/10.3390/cells10071842 - 20 Jul 2021
Viewed by 827
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 [...] Read more.
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
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