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Special Issue "The World of Transglutaminases: From Basic Biological and Medical Research to Applied Sciences 2.0"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 8522

Special Issue Editors

Department of Chemistry and Biology, University of Salerno, via Giovanni Paolo II 132, 84084 Fisciano, SA, Italy
Interests: tissue transglutaminase (tTG); anti-tTG antibodies and gliadin peptides in celiac disease; effects of pollutants; chemicals and bioactive compounds in cell and animal models
Special Issues, Collections and Topics in MDPI journals
Department of Chemistry and Biology, University of Salerno, via Giovanni Paolo II 132, 84084 Fisciano, SA, Italy
Interests: transglutaminase and anti-tTG in celiac disease; interplay between transglutaminase and gliadin peptides in celiac disease; modulation of cell functions by environmental polluttants; phosphoproteomics; miRNA
Special Issues, Collections and Topics in MDPI journals
Department of Chemistry and Biology, University of Salerno, via Giovanni Paolo II 132, 84084, Fisciano, SA, Italy
Interests: anti-tissue transglutaminase and angiogenesis in celiac disease; modulation of tTG function by autoantibodies; cell stress and human diseases; TBX1 gene function in angiogenesis and lymphangiogenesis in mouse models; molecular mechanisms of bioactive compounds from plants
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Transglutaminases are important protein-modifying enzymes that are distributed in all kingdoms of life. The post-translational modifications catalyzed by these enzymes produce stable networks in the extracellular matrix, in body fluids, and inside cells, thus contributing to the regulation of many aspects of cell life and death. Besides the cross-linking function, other enzymatic reactions and non-enzymatic functions can be attributed to some members of the transglutaminase family. In this regard, the ubiquitous multi-functional tissue transglutaminase has been nicknamed "the bete noire" of the family or "a molecular swiss army knife." Evidence on the involvement of transglutaminases in human diseases, such as cancer, fibrosis, and neurodegenerative and autoimmune diseases, is rapidly increasing. Moreover, transglutaminases have been successfully employed as biotechnological tools in several industrial fields.

The aim of this Special Issue is to collect original and review articles on all aspects of research on the transglutaminases family, from basic research to biomedical and biotechnological applications.

Suggested topics include, but are not limited to:

  • Transglutaminases in bacteria, plants, and other lower, non-mammalian organisms;
  • The discovery of novel transglutaminases;
  • Mammalian transglutaminases—new functions for old enzymes;
  • The thousand faces of the tissue transglutaminase;
  • Transglutaminases in human diseases;
  • Transglutaminases as therapeutic targets;
  • Transglutaminases as biotechnological tools.

Prof. Ivana Caputo
Dr. Gaetana Paolella
Dr. Stefania Martucciello
Guest Editors

Manuscript Submission Information

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Published Papers (6 papers)

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Research

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Article
Transglutaminase Activity Is Conserved in Stratified Epithelia and Skin Appendages of Mammals and Birds
Int. J. Mol. Sci. 2023, 24(3), 2193; https://doi.org/10.3390/ijms24032193 - 22 Jan 2023
Viewed by 613
Abstract
The cross-linking of structural proteins is critical for establishing the mechanical stability of the epithelial compartments of the skin and skin appendages. The introduction of isopeptide bonds between glutamine and lysine residues depends on catalysis by transglutaminases and represents the main protein cross-linking [...] Read more.
The cross-linking of structural proteins is critical for establishing the mechanical stability of the epithelial compartments of the skin and skin appendages. The introduction of isopeptide bonds between glutamine and lysine residues depends on catalysis by transglutaminases and represents the main protein cross-linking mechanism besides the formation of disulfide bonds. Here, we used a fluorescent labeling protocol to localize the activity of transglutaminases on thin sections of the integument and its appendages in mammals and birds. In human tissues, transglutaminase activity was detected in the granular layer of the epidermis, suprabasal layers of the gingival epithelium, the duct of sweat glands, hair follicles and the nail matrix. In the skin appendages of chickens, transglutaminase activity was present in the claw matrix, the feather follicle sheath, the feather sheath and in differentiating keratinocytes of feather barb ridges. During chicken embryogenesis, active transglutaminase was found in the cornifying epidermis, the periderm and the subperiderm. Transglutaminase activity was also detected in the filiform papillae on the tongue of mice and in conical papillae on the tongue of chickens. In summary, our study reveals that transglutaminase activities are widely distributed in integumentary structures and suggests that transglutamination contributes to the cornification of hard skin appendages such as nails and feathers. Full article
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Article
The Effect of Activated FXIII, a Transglutaminase, on Vascular Smooth Muscle Cells
Int. J. Mol. Sci. 2022, 23(10), 5845; https://doi.org/10.3390/ijms23105845 - 23 May 2022
Viewed by 1133
Abstract
Plasma factor XIII (pFXIII) is a heterotetramer of FXIII-A and FXIII-B subunits. The cellular form (cFXIII), a dimer of FXIII-A, is present in a number of cell types. Activated FXIII (FXIIIa), a transglutaminase, plays an important role in clot stabilization, wound healing, angiogenesis [...] Read more.
Plasma factor XIII (pFXIII) is a heterotetramer of FXIII-A and FXIII-B subunits. The cellular form (cFXIII), a dimer of FXIII-A, is present in a number of cell types. Activated FXIII (FXIIIa), a transglutaminase, plays an important role in clot stabilization, wound healing, angiogenesis and maintenance of pregnancy. It has a direct effect on vascular endothelial cells and fibroblasts, which have been implicated in the development of atherosclerotic plaques. Our aim was to explore the effect of FXIIIa on human aortic smooth muscle cells (HAoSMCs), another major cell type in the atherosclerotic plaque. Osteoblastic transformation induced by Pi and Ca2+ failed to elicit the expression of cFXIII in HAoSMCs. EZ4U, CCK-8 and CytoSelect Wound Healing assays were used to investigate cell proliferation and migration. The Sircol Collagen Assay Kit was used to monitor collagen secretion. Thrombospondin-1 (TSP-1) levels were measured by ELISA. Cell-associated TSP-1 was detected by the immunofluorescence technique. The TSP-1 mRNA level was estimated by RT-qPCR. Activated recombinant cFXIII (rFXIIIa) increased cell proliferation and collagen secretion. In parallel, a 67% decrease in TSP-1 concentration in the medium and a 2.5-fold increase in cells were observed. TSP-1 mRNA did not change significantly. These effects of FXIIIa might contribute to the pathogenesis of atherosclerotic plaques. Full article
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Article
Tissue Transglutaminase Knock-Out Preadipocytes and Beige Cells of Epididymal Fat Origin Possess Decreased Mitochondrial Functions Required for Thermogenesis
Int. J. Mol. Sci. 2022, 23(9), 5175; https://doi.org/10.3390/ijms23095175 - 05 May 2022
Viewed by 1470
Abstract
Beige adipocytes with thermogenic function are activated during cold exposure in white adipose tissue through the process of browning. These cells, similar to brown adipocytes, dissipate stored chemical energy in the form of heat with the help of uncoupling protein 1 (UCP1). Recently, [...] Read more.
Beige adipocytes with thermogenic function are activated during cold exposure in white adipose tissue through the process of browning. These cells, similar to brown adipocytes, dissipate stored chemical energy in the form of heat with the help of uncoupling protein 1 (UCP1). Recently, we have shown that tissue transglutaminase (TG2) knock-out mice have decreased cold tolerance in parallel with lower utilization of their epididymal adipose tissue and reduced browning. To learn more about the thermogenic function of this fat depot, we isolated preadipocytes from the epididymal adipose tissue of wild-type and TG2 knock-out mice and differentiated them in the beige direction. Although differentiation of TG2 knock-out preadipocytes is phenotypically similar to the wild-type cells, the mitochondria of the knock-out beige cells have multiple impairments including an altered electron transport system generating lower electrochemical potential difference, reduced oxygen consumption, lower UCP1 protein content, and a higher portion of fragmented mitochondria. Most of these differences are present in preadipocytes as well, and the differentiation process cannot overcome the functional disadvantages completely. TG2 knock-out beige adipocytes produce more iodothyronine deiodinase 3 (DIO3) which may inactivate thyroid hormones required for the establishment of optimal mitochondrial function. The TG2 knock-out preadipocytes and beige cells are both hypometabolic as compared with the wild-type controls which may also be explained by the lower expression of solute carrier proteins SLC25A45, SLC25A47, and SLC25A42 which transport acylcarnitine, Co-A, and amino acids into the mitochondrial matrix. As a consequence, the mitochondria in TG2 knock-out beige adipocytes probably cannot reach the energy-producing threshold required for normal thermogenic functions, which may contribute to the decreased cold tolerance of TG2 knock-out mice. Full article
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Article
Biochemical Characterisation of Human Transglutaminase 4
Int. J. Mol. Sci. 2021, 22(22), 12448; https://doi.org/10.3390/ijms222212448 - 18 Nov 2021
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Abstract
Transglutaminases are protein-modifying enzymes involved in physiological and pathological processes with potent therapeutic possibilities. Human TG4, also called prostate transglutaminase, is involved in the development of autoimmune and tumour diseases. Although rodent TG4 is well characterised, biochemical characteristics of human TG4 that could [...] Read more.
Transglutaminases are protein-modifying enzymes involved in physiological and pathological processes with potent therapeutic possibilities. Human TG4, also called prostate transglutaminase, is involved in the development of autoimmune and tumour diseases. Although rodent TG4 is well characterised, biochemical characteristics of human TG4 that could help th e understanding of its way of action are not published. First, we analysed proteomics databases and found that TG4 protein is present in human tissues beyond the prostate. Then, we studied in vitro the transamidase activity of human TG4 and its regulation using the microtitre plate method. Human TG4 has low transamidase activity which prefers slightly acidic pH and a reducing environment. It is enhanced by submicellar concentrations of SDS suggesting that membrane proximity is an important regulatory event. Human TG4 does not bind GTP as tested by GTP-agarose and BODIPY-FL-GTPγS binding, and its proteolytic activation by dispase or when expressed in AD-293 cells was not observed either. We identified several potential human TG4 glutamine donor substrates in the AD-293 cell extract by biotin-pentylamine incorporation and mass spectrometry. Several of these potential substrates are involved in cell–cell interaction, adhesion and proliferation, suggesting that human TG4 could become an anticancer therapeutic target. Full article
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Article
Transamidation Down-Regulates Intestinal Immunity of Recombinant α-Gliadin in HLA-DQ8 Transgenic Mice
Int. J. Mol. Sci. 2021, 22(13), 7019; https://doi.org/10.3390/ijms22137019 - 29 Jun 2021
Cited by 5 | Viewed by 1610
Abstract
Enzymatic transamidation of gliadins by microbial transglutaminase (mTG) inhibits interferon-γ (IFN-γ) secretion by intestinal T cell lines in patients with celiac disease (CD). To gain insight into the cellular mechanisms underlying the down-regulatory effects of transamidation, we tested a single recombinant α-gliadin (r-gliadin) [...] Read more.
Enzymatic transamidation of gliadins by microbial transglutaminase (mTG) inhibits interferon-γ (IFN-γ) secretion by intestinal T cell lines in patients with celiac disease (CD). To gain insight into the cellular mechanisms underlying the down-regulatory effects of transamidation, we tested a single recombinant α-gliadin (r-gliadin) harbouring two immunodominant peptides, p13 (aa. 120–139) and p23 (aa. 220–239), in HLA-DQ8 transgenic mice, a model of gluten sensitivity. Mice were intranasally immunised with r-gliadin or r-gliadin transamidated by mTG (K-r-gliadin) along with cholera toxin, and the response of mesenteric lymph node cells was analysed by cytokine multiplex assay. An in vitro challenge with r-gliadin was characterised by secretion of specific cytokines featuring both innate immunity and the Th1/Th2/Th17 pattern of the adaptive response. Notably, transamidation specifically down-regulated the Th1 response. Structural studies performed on K-r-gliadin confirmed that specific glutamine residues in p13 and p23, previously found to be deamidated by tissue transglutaminase, were also transamidated by mTG. In silico analysis, simulating p13 and p23 peptide binding to HLA-DQ8 showed that these glutamines, in the form of glutamate, could interact by means of salt bridges with peculiar amino acids of the alpha chain of HLA-DQ8, suggesting that their transamidation may influence the HLA-restricted recognition of these peptides. Thus, the structural findings provided a rationale to explain the down-regulation of the r-gliadin-specific Th1 response following transamidation. Full article
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Review

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Review
Type 2 Transglutaminase in Coeliac Disease: A Key Player in Pathogenesis, Diagnosis and Therapy
Int. J. Mol. Sci. 2022, 23(14), 7513; https://doi.org/10.3390/ijms23147513 - 06 Jul 2022
Cited by 5 | Viewed by 1361
Abstract
Type 2 transglutaminase (TG2) is the main autoantigen in coeliac disease (CD), a widespread inflammatory enteropathy caused by the ingestion of gluten-containing cereals in genetically predisposed individuals. As a consequence, serum antibodies to TG2 represent a very useful marker in CD diagnosis. However, [...] Read more.
Type 2 transglutaminase (TG2) is the main autoantigen in coeliac disease (CD), a widespread inflammatory enteropathy caused by the ingestion of gluten-containing cereals in genetically predisposed individuals. As a consequence, serum antibodies to TG2 represent a very useful marker in CD diagnosis. However, TG2 is also an important player in CD pathogenesis, for its ability to deamidate some Gln residues of gluten peptides, which become more immunogenic in CD intestinal mucosa. Given the importance of TG2 enzymatic activities in CD, several studies have sought to discover specific and potent inhibitors that could be employed in new therapeutical approaches for CD, as alternatives to a lifelong gluten-free diet. In this review, we summarise all the aspects regarding TG2 involvement in CD, including its enzymatic reactions in pathogenesis, the role of anti-TG2 antibodies in disease management, and the exploration of recent strategies to reduce deamidation or to use transamidation to detoxify gluten. Full article
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