Special Issue "Transglutaminases in Health and Disease"

A special issue of Medical Sciences (ISSN 2076-3271).

Deadline for manuscript submissions: closed (31 October 2018).

Special Issue Editors

Prof. Simone Beninati
E-Mail Website
Guest Editor
Prof. Carlo Mischiati
E-Mail Website
Guest Editor
Dept.of Biomedical Sciences and Surgical Specialties, Faculty of Medicine, Pharmacy and Prevention, University of Ferrara, Ferrara, Italy
Interests: molecular medicine, molecular mechanisms of disease pathogenesis, development of molecular diagnosis, novel approaches to rational treatment.

Special Issue Information

Dear Colleagues,

Transglutaminases belong to a large family of intracellular and extracellular Ca2+- dependent enzymes, which catalyze the post-translational modification of many substrate proteins. At present, significant progress has been made in understanding the biological role of most mammalian transglutaminase isoforms. Recent findings suggest new scenarios, in particular for ubiquitous tissue transglutaminase. In fact, several studies have shown that some transglutaminases normally present at low levels in many tissues, are activated and/or overexpressed in a wide variety of human diseases thus paving the way for new therapeutic possibilities. In addition, as with all enzymes that exert their metabolic function by modifying properties of target proteins, the identification and the characterization of the modified proteins will allow to shed new light on the functions of the transglutaminase and to understand better their involvement in human diseases.

In light of this, I am pleased to invite you to contribute to this Special Issue, "Transglutaminases in Health and Disease", which will be published in the international journal Medical Sciences. Medical Sciences is an international open access scientific journal, providing platform for advances in basic, translational and clinical research. Citations are available in PubMed and full-text are archived in PubMed Central. The journal aims is to publish original research, review articles and short communications about molecular and cellular processes in disease, in order to increase understanding of the fundamental principles and biological questions of medicine. The objectives of this Special issue on "Transglutaminases in Health and Disease" are to publish and collect both experimental and theoretical contributions from original and high-quality research articles and encourage researchers to investigate topics in the field of transglutaminases in various diseases.

Prof. Simone Beninati
Lead Guest Editor

Prof. Carlo Mischiati
Co-Guest Editor

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 papers will be 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. Medical Sciences 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 1000 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.

Published Papers (8 papers)

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Research

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Open AccessArticle
Differential Expression of Tissue Transglutaminase Splice Variants in Peripheral Blood Mononuclear Cells of Primary Progressive Multiple Sclerosis Patients
Med. Sci. 2018, 6(4), 108; https://doi.org/10.3390/medsci6040108 - 27 Nov 2018
Cited by 1
Abstract
Multiple Sclerosis (MS) is an inflammatory and neurodegenerative disorder of the central nervous system (CNS) characterized by inflammation and immune cell infiltration in the brain parenchyma. Tissue transglutaminase (TG2), a calcium-dependent cross-linking enzyme, has been shown to be present in infiltrating MHC-II positive [...] Read more.
Multiple Sclerosis (MS) is an inflammatory and neurodegenerative disorder of the central nervous system (CNS) characterized by inflammation and immune cell infiltration in the brain parenchyma. Tissue transglutaminase (TG2), a calcium-dependent cross-linking enzyme, has been shown to be present in infiltrating MHC-II positive cells in lesions of patients suffering from MS. Moreover, TG2 mRNA levels in peripheral blood mononuclear cells (PBMC)-derived from primary progressive (PP)-MS patients correlated with clinical parameters, thus highlighting the importance of TG2 in MS pathology. In the present study, we further characterized TG2 expression by measuring the mRNA levels of full-length TG2 and four TG2 alternative splice variants in PBMCs derived from PP-MS patients and healthy control (HC) subjects. In PP-MS-derived PBMCs, TG2 variant V4b was significantly higher expressed, and both V4a and V4b variants were relatively more expressed in relation to full-length TG2. These observations open new avenues to unravel the importance of TG2 alternative splicing in the pathophysiology of PP-MS. Full article
(This article belongs to the Special Issue Transglutaminases in Health and Disease)
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Open AccessArticle
Transglutaminase 2 Up-Regulation Is Associated with Inflammatory Response in PBMC from Healthy Subjects with Hypovitaminosis D
Med. Sci. 2018, 6(4), 103; https://doi.org/10.3390/medsci6040103 - 16 Nov 2018
Abstract
Recent evidence indicated that transglutaminase 2 (TG2) is involved in the adaptive immune response. Peripheral blood mononuclear cells (PBMC) have largely been used to characterize molecular mechanisms occurring in the activation of immune response. Given that the maintenance of immune system functions requires [...] Read more.
Recent evidence indicated that transglutaminase 2 (TG2) is involved in the adaptive immune response. Peripheral blood mononuclear cells (PBMC) have largely been used to characterize molecular mechanisms occurring in the activation of immune response. Given that the maintenance of immune system functions requires an optimal vitamin D status, we aimed to assess the involvement of TG2/NF-κB signaling in cytokine production in PBMC isolated from adult subjects with different vitamin D status. We observed TG2 up-regulation and a significant positive correlation between TG2 expression and tumor necrosis factor (TNF)-α mRNA levels in PBMC of recruited patients. The mRNA levels of TG2 and TNF-α were higher in PBMC of subjects having hypovitaminosis D, namely plasma 25(OH)vitamin D3 levels lower than 50 nmol/L, than in those with normal vitamin D levels. Moreover, NF-κB up-regulation and nuclear translocation were detected, concomitantly with TG2 as well as TNF-α increased expression, in PBMC of vitamin D-deficient subjects. The present findings confirm that an increase in TG2 expression exacerbates the activation of NF-κB and the production of pro-inflammatory cytokines, and suggest a link between vitamin D deficiency, TG2 up-regulation, and inflammation. Full article
(This article belongs to the Special Issue Transglutaminases in Health and Disease)
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Review

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Open AccessReview
Transglutaminase 2: The Maestro of the Oncogenic Mediators in Renal Cell Carcinoma
Med. Sci. 2019, 7(2), 24; https://doi.org/10.3390/medsci7020024 - 06 Feb 2019
Abstract
Transglutaminase 2 (TG2) is a multifunctional crosslinking enzyme that displays transamidation, protein disulfide isomerase, protein kinase, as well as GTPase and ATPase activities. TG2 can also act as an adhesion molecule involved in the syndecan and integrin receptor signaling. In recent years, TG2 [...] Read more.
Transglutaminase 2 (TG2) is a multifunctional crosslinking enzyme that displays transamidation, protein disulfide isomerase, protein kinase, as well as GTPase and ATPase activities. TG2 can also act as an adhesion molecule involved in the syndecan and integrin receptor signaling. In recent years, TG2 was implicated in cancer progression, survival, invasion, migration, and stemness of many cancer types, including renal cell carcinoma (RCC). Von Hippel-Lindau mutations leading to the subsequent activation of Hypoxia Inducible Factor (HIF)-1-mediated signaling pathways, survival signaling via the PI3K/Akt pathway resulting in Epithelial Mesenchymal Transition (EMT) metastasis and angiogenesis are the main factors in RCC progression. A number of studies have shown that TG2 was important in HIF-1- and PI3K-mediated signaling, VHL and p53 stabilization, glycolytic metabolism and migratory phenotype in RCC. This review focuses on the role of TG2 in the regulation of molecular pathways nurturing not only the development and propagation of RCC, but also drug-resistance and metastatic potential. Full article
(This article belongs to the Special Issue Transglutaminases in Health and Disease)
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Open AccessFeature PaperReview
The Role of Tissue Transglutaminase in Cancer Cell Initiation, Survival and Progression
Med. Sci. 2019, 7(2), 19; https://doi.org/10.3390/medsci7020019 - 25 Jan 2019
Cited by 2
Abstract
Tissue transglutaminase (transglutaminase type 2; TG2) is the most ubiquitously expressed member of the transglutaminase family (EC 2.3.2.13) that catalyzes specific post-translational modifications of proteins through a calcium-dependent acyl-transfer reaction (transamidation). In addition, this enzyme displays multiple additional enzymatic activities, such as guanine [...] Read more.
Tissue transglutaminase (transglutaminase type 2; TG2) is the most ubiquitously expressed member of the transglutaminase family (EC 2.3.2.13) that catalyzes specific post-translational modifications of proteins through a calcium-dependent acyl-transfer reaction (transamidation). In addition, this enzyme displays multiple additional enzymatic activities, such as guanine nucleotide binding and hydrolysis, protein kinase, disulfide isomerase activities, and is involved in cell adhesion. Transglutaminase 2 has been reported as one of key enzymes that is involved in all stages of carcinogenesis; the molecular mechanisms of action and physiopathological effects depend on its expression or activities, cellular localization, and specific cancer model. Since it has been reported as both a potential tumor suppressor and a tumor-promoting factor, the role of this enzyme in cancer is still controversial. Indeed, TG2 overexpression has been frequently associated with cancer stem cells’ survival, inflammation, metastatic spread, and drug resistance. On the other hand, the use of inducers of TG2 transamidating activity seems to inhibit tumor cell plasticity and invasion. This review covers the extensive and rapidly growing field of the role of TG2 in cancer stem cells survival and epithelial–mesenchymal transition, apoptosis and differentiation, and formation of aggressive metastatic phenotypes. Full article
(This article belongs to the Special Issue Transglutaminases in Health and Disease)
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Open AccessReview
Spotlight on the Transglutaminase 2-Heparan Sulfate Interaction
Med. Sci. 2019, 7(1), 5; https://doi.org/10.3390/medsci7010005 - 04 Jan 2019
Abstract
Heparan sulfate proteoglycans (HSPGs), syndecan-4 (Sdc4) especially, have been suggested as potential partners of transglutaminase-2 (TG2) in kidney and cardiac fibrosis, metastatic cancer, neurodegeneration and coeliac disease. The proposed role for HSPGs in the trafficking of TG2 at the cell surface and in [...] Read more.
Heparan sulfate proteoglycans (HSPGs), syndecan-4 (Sdc4) especially, have been suggested as potential partners of transglutaminase-2 (TG2) in kidney and cardiac fibrosis, metastatic cancer, neurodegeneration and coeliac disease. The proposed role for HSPGs in the trafficking of TG2 at the cell surface and in the extracellular matrix (ECM) has been linked to the fibrogenic action of TG2 in experimental models of kidney fibrosis. As the TG2-HSPG interaction is largely mediated by the heparan sulfate (HS) chains of proteoglycans, in the past few years a number of studies have investigated the affinity of TG2 for HS, and the TG2 heparin binding site has been mapped with alternative outlooks. In this review, we aim to provide a compendium of the main literature available on the interaction of TG2 with HS, with reference to the pathological processes in which extracellular TG2 plays a role. Full article
(This article belongs to the Special Issue Transglutaminases in Health and Disease)
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Open AccessReview
Transglutaminases in Monocytes and Macrophages
Med. Sci. 2018, 6(4), 115; https://doi.org/10.3390/medsci6040115 - 11 Dec 2018
Cited by 1
Abstract
Macrophages are key players in various inflammatory disorders and pathological conditions via phagocytosis and orchestrating immune responses. They are highly heterogeneous in terms of their phenotypes and functions by adaptation to different organs and tissue environments. Upon damage or infection, monocytes are rapidly [...] Read more.
Macrophages are key players in various inflammatory disorders and pathological conditions via phagocytosis and orchestrating immune responses. They are highly heterogeneous in terms of their phenotypes and functions by adaptation to different organs and tissue environments. Upon damage or infection, monocytes are rapidly recruited to tissues and differentiate into macrophages. Transglutaminases (TGs) are a family of structurally and functionally related enzymes with Ca2+-dependent transamidation and deamidation activity. Numerous studies have shown that TGs, particularly TG2 and Factor XIII-A, are extensively involved in monocyte- and macrophage-mediated physiological and pathological processes. In the present review, we outline the current knowledge of the role of TGs in the adhesion and extravasation of monocytes, the expression of TGs during macrophage differentiation, and the regulation of TG2 expression by various pro- and anti-inflammatory mediators in macrophages. Furthermore, we summarize the role of TGs in macrophage phagocytosis and the understanding of the mechanisms involved. Finally, we review the roles of TGs in tissue-specific macrophages, including monocytes/macrophages in vasculature, alveolar and interstitial macrophages in lung, microglia and infiltrated monocytes/macrophages in central nervous system, and osteoclasts in bone. Based on the studies in this review, we conclude that monocyte- and macrophage-derived TGs are involved in inflammatory processes in these organs. However, more in vivo studies and clinical studies during different stages of these processes are required to determine the accurate roles of TGs, their substrates, and the mechanisms-of-action. Full article
(This article belongs to the Special Issue Transglutaminases in Health and Disease)
Open AccessReview
New Insights into Development of Transglutaminase 2 Inhibitors as Pharmaceutical Lead Compounds
Med. Sci. 2018, 6(4), 87; https://doi.org/10.3390/medsci6040087 - 08 Oct 2018
Cited by 2
Abstract
Transglutaminase 2 (EC 2.3.2.13; TG2 or TGase 2) plays important roles in the pathogenesis of many diseases, including cancers, neurodegeneration, and inflammatory disorders. Under normal conditions, however, mice lacking TGase 2 exhibit no obvious abnormal phenotype. TGase 2 expression is induced by chemical, [...] Read more.
Transglutaminase 2 (EC 2.3.2.13; TG2 or TGase 2) plays important roles in the pathogenesis of many diseases, including cancers, neurodegeneration, and inflammatory disorders. Under normal conditions, however, mice lacking TGase 2 exhibit no obvious abnormal phenotype. TGase 2 expression is induced by chemical, physical, and viral stresses through tissue-protective signaling pathways. After stress dissipates, expression is normalized by feedback mechanisms. Dysregulation of TGase 2 expression under pathologic conditions, however, can potentiate pathogenesis and aggravate disease severity. Consistent with this, TGase 2 knockout mice exhibit reversal of disease phenotypes in neurodegenerative and chronic inflammatory disease models. Accordingly, TGase 2 is considered to be a potential therapeutic target. Based on structure–activity relationship assays performed over the past few decades, TGase 2 inhibitors have been developed that target the enzyme’s active site, but clinically applicable inhibitors are not yet available. The recently described the small molecule GK921, which lacks a group that can react with the active site of TGase 2, and efficiently inhibits the enzyme’s activity. Mechanistic studies revealed that GK921 binds at an allosteric binding site in the N-terminus of TGase 2 (amino acids (a.a.) 81–116), triggering a conformational change that inactivates the enzyme. Because the binding site of GK921 overlaps with the p53-binding site of TGase 2, the drug induces apoptosis in renal cell carcinoma by stabilizing p53. In this review, we discuss the possibility of developing TGase 2 inhibitors that target the allosteric binding site of TGase 2. Full article
(This article belongs to the Special Issue Transglutaminases in Health and Disease)
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Open AccessReview
Role of Transglutaminase 2 in Migration of Tumor Cells and How Mouse Models Fit
Med. Sci. 2018, 6(3), 70; https://doi.org/10.3390/medsci6030070 - 30 Aug 2018
Abstract
A search for the “magic bullet”, a molecule, the targeting abilities of which could stop the migration of tumor cells, is currently underway, but remains in the early stages. There are still many unknowns regarding the cell migration. The main approach is the [...] Read more.
A search for the “magic bullet”, a molecule, the targeting abilities of which could stop the migration of tumor cells, is currently underway, but remains in the early stages. There are still many unknowns regarding the cell migration. The main approach is the employment of mouse models, that are sources of valuable information, but still cannot answer all of the questions. One of the molecules of interest is Transglutaminase 2 (TG2). It is a well-described molecule involved in numerous pathways and elevated in metastatic tumors. The question remains whether mice and humans can give the same answer considering TG2. Full article
(This article belongs to the Special Issue Transglutaminases in Health and Disease)
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