Research

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20 pages, 8074 KiB

Open AccessArticle

Transglutaminases and Obesity in Humans: Association of F13A1 to Adipocyte Hypertrophy and Adipose Tissue Immune Response

by Mari T. Kaartinen, Mansi Arora, Sini Heinonen, Aila Rissanen, Jaakko Kaprio and Kirsi H. Pietiläinen

Int. J. Mol. Sci. 2020, 21(21), 8289; https://doi.org/10.3390/ijms21218289 - 05 Nov 2020

Cited by 14 | Viewed by 3163

Abstract

Transglutaminases TG2 and FXIII-A have recently been linked to adipose tissue biology and obesity, however, human studies for TG family members in adipocytes have not been conducted. In this study, we investigated the association of TGM family members to acquired weight gain in [...] Read more.

Transglutaminases TG2 and FXIII-A have recently been linked to adipose tissue biology and obesity, however, human studies for TG family members in adipocytes have not been conducted. In this study, we investigated the association of TGM family members to acquired weight gain in a rare set of monozygotic (MZ) twins discordant for body weight, i.e., heavy–lean twin pairs. We report that F13A1 is the only TGM family member showing significantly altered, higher expression in adipose tissue of the heavier twin. Our previous work linked adipocyte F13A1 to increased weight, body fat mass, adipocyte size, and pro-inflammatory pathways. Here, we explored further the link of F13A1 to adipocyte size in the MZ twins via a previously conducted TWA study that was further mined for genes that specifically associate to hypertrophic adipocytes. We report that differential expression of F13A1 (ΔHeavy–Lean) associated with 47 genes which were linked via gene enrichment analysis to immune response, leucocyte and neutrophil activation, as well as cytokine response and signaling. Our work brings further support to the role of F13A1 in the human adipose tissue pathology, suggesting a role in the cascade that links hypertrophic adipocytes with inflammation. Full article

(This article belongs to the Special Issue The World of Transglutaminases: From Basic Biological and Medical Research to Applied Sciences)

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13 pages, 4019 KiB

Open AccessArticle

Constitutive Differential Features of Type 2 Transglutaminase in Cells Derived from Celiac Patients and from Healthy Subjects

by Gaetana Paolella, Merlin Nanayakkara, Silvia Sposito, Marilena Lepretti, Salvatore Auricchio, Carla Esposito, Maria Vittoria Barone, Stefania Martucciello and Ivana Caputo

Int. J. Mol. Sci. 2020, 21(4), 1231; https://doi.org/10.3390/ijms21041231 - 12 Feb 2020

Cited by 6 | Viewed by 2210

Abstract

Type 2 transglutaminase (TG2) is a ubiquitous enzyme able to modify gliadin peptides introduced into the organism through the diet. By means of its catalytic activity, TG2 seems to have an important pathogenetic role in celiac disease (CD), an inflammatory intestinal disease caused [...] Read more.

Type 2 transglutaminase (TG2) is a ubiquitous enzyme able to modify gliadin peptides introduced into the organism through the diet. By means of its catalytic activity, TG2 seems to have an important pathogenetic role in celiac disease (CD), an inflammatory intestinal disease caused by the ingestion of gluten-containing cereals. A strong autoimmune response to TG2 characterizes CD development. Anti-TG2 antibodies specifically derange the uptake of the α-gliadin peptide 31–43 by control, but not by celiac dermal fibroblasts, underlying some different constitutive features regarding TG2 in healthy and celiac subjects. Our aim was to investigate whether these differences depended on a different TG2 subcellular distribution and whether peptide 31–43 differentially regulated TG2 expression and activity in cells of the two groups of subjects. We found that TG2 was more abundantly associated with membranes of celiac fibroblasts than of control cells, in particular with the early endosomal and autophagic compartments. We also found that peptide 31–43 differentially affected TG2 expression and activity in the two groups of cells, activating TG2 more in control than in celiac cells and inducing TG2 expression in celiac cells, but not in control ones. The different TG2 subcellular localization and the different way the peptide 31–43 modulates TG2 activity and availability into control and CD cells suggested that TG2 is involved in the definition of a constitutive CD cellular phenotype, thus having an important and still undefined role in CD pathogenesis. Full article

(This article belongs to the Special Issue The World of Transglutaminases: From Basic Biological and Medical Research to Applied Sciences)

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17 pages, 6360 KiB

Open AccessArticle

Cellular Factor XIII, a Transglutaminase in Human Corneal Keratocytes

by Zsuzsanna Z. Orosz, Helga Bárdos, Amir H. Shemirani, Ildikó Beke Debreceni, Riitta Lassila, Antti S. Riikonen, Johanna A. Kremer Hovinga, Theo G. Seiler, Hendrika A. van Dorland, Verena Schroeder, Zoltán Boda, László Nemes, Beatrice Früh Eppstein, Bence Nagy, Andrea Facskó, János Kappelmayer and László Muszbek

Int. J. Mol. Sci. 2019, 20(23), 5963; https://doi.org/10.3390/ijms20235963 - 27 Nov 2019

Cited by 6 | Viewed by 3339

Abstract

Cellular factor XIII (cFXIII, FXIII-A₂), a transglutaminase, has been demonstrated in a few cell types. Its main function is to cross-link proteins by isopeptide bonds. Here, we investigated the presence of cFXIII in cells of human cornea. Tissue sections of the [...] Read more.

Cellular factor XIII (cFXIII, FXIII-A₂), a transglutaminase, has been demonstrated in a few cell types. Its main function is to cross-link proteins by isopeptide bonds. Here, we investigated the presence of cFXIII in cells of human cornea. Tissue sections of the cornea were immunostained for FXIII-A in combination with staining for CD34 antigen or isopeptide cross-links. Isolated corneal keratocytes were also evaluated by immunofluorescent microscopy and flow cytometry. FXIII-A in the corneal stroma was quantified by Western blotting. FXIII-A mRNA was detected by RT-qPCR. The cornea of FXIII-A-deficient patients was evaluated by cornea topography. FXIII-A was detected in 68 ± 13% of CD34+ keratocytes. Their distribution in the corneal stroma was unequal; they were most abundant in the subepithelial tertile. cFXIII was of cytoplasmic localization. In the stroma, 3.64 ng cFXIII/mg protein was measured. The synthesis of cFXIII by keratocytes was confirmed by RT-qPCR. Isopeptide cross-links were detected above, but not within the corneal stroma. Slight abnormality of the cornea was detected in six out of nine FXIII-A-deficient patients. The presence of cFXIII in human keratocytes was established for the first time. cFXIII might be involved in maintaining the stability of the cornea and in the corneal wound healing process. Full article

(This article belongs to the Special Issue The World of Transglutaminases: From Basic Biological and Medical Research to Applied Sciences)

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Review

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18 pages, 691 KiB

Open AccessReview

Interplay between Type 2 Transglutaminase (TG2), Gliadin Peptide 31-43 and Anti-TG2 Antibodies in Celiac Disease

by Stefania Martucciello, Silvia Sposito, Carla Esposito, Gaetana Paolella and Ivana Caputo

Int. J. Mol. Sci. 2020, 21(10), 3673; https://doi.org/10.3390/ijms21103673 - 23 May 2020

Cited by 9 | Viewed by 3100

Abstract

Celiac disease (CD) is a common intestinal inflammatory disease involving both a genetic background and environmental triggers. The ingestion of gluten, a proteic component of several cereals, represents the main hexogen factor implied in CD onset that involves concomitant innate and adaptive immune [...] Read more.

Celiac disease (CD) is a common intestinal inflammatory disease involving both a genetic background and environmental triggers. The ingestion of gluten, a proteic component of several cereals, represents the main hexogen factor implied in CD onset that involves concomitant innate and adaptive immune responses to gluten. Immunogenicity of some gluten sequences are strongly enhanced as the consequence of the deamidation of specific glutamine residues by type 2 transglutaminase (TG2), a ubiquitous enzyme whose expression is up-regulated in the intestine of CD patients. A short gluten sequence resistant to intestinal proteases, the α-gliadin peptide 31-43, seems to modulate TG2 function in the gut; on the other hand, the enzyme can affect the biological activity of this peptide. In addition, an intense auto-immune response towards TG2 is a hallmark of CD. Auto-antibodies exert a range of biological effects on several cells, effects that in part overlap with those induced by peptide 31-43. In this review, we delineate a scenario in which TG2, anti-TG2 antibodies and peptide 31-43 closely relate to each other, thus synergistically participating in CD starting and progression. Full article

(This article belongs to the Special Issue The World of Transglutaminases: From Basic Biological and Medical Research to Applied Sciences)

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17 pages, 1267 KiB

Open AccessReview

Microbial Transglutaminase as a Tool to Improve the Features of Hydrocolloid-Based Bioplastics

by C. Valeria L. Giosafatto, Antonio Fusco, Asmaa Al-Asmar and Loredana Mariniello

Int. J. Mol. Sci. 2020, 21(10), 3656; https://doi.org/10.3390/ijms21103656 - 22 May 2020

Cited by 16 | Viewed by 4356

Abstract

Several proteins from animal and plant origin act as microbial transglutaminase substrate, a crosslinking enzyme capable of introducing isopeptide bonds into proteins between the aminoacids glutamines and lysines. This feature has been widely exploited to modify the biological properties of many proteins, such [...] Read more.

Several proteins from animal and plant origin act as microbial transglutaminase substrate, a crosslinking enzyme capable of introducing isopeptide bonds into proteins between the aminoacids glutamines and lysines. This feature has been widely exploited to modify the biological properties of many proteins, such as emulsifying, gelling, viscosity, and foaming. Besides, microbial transglutaminase has been used to prepare bioplastics that, because made of renewable molecules, are able to replace the high polluting plastics of petrochemical origin. In fact, most of the time, it has been shown that the microbial enzyme strengthens the matrix of protein-based bioplastics, thus, influencing the technological characteristics of the derived materials. In this review, an overview of the ability of many proteins to behave as good substrates of the enzyme and their ability to give rise to bioplastics with improved properties is presented. Different applications of this enzyme confirm its important role as an additive to recover high value-added protein containing by-products with a double aim (i) to produce environmentally friendly materials and (ii) to find alternative uses of wastes as renewable, cheap, and non-polluting sources. Both principles are in line with the bio-economy paradigm. Full article

(This article belongs to the Special Issue The World of Transglutaminases: From Basic Biological and Medical Research to Applied Sciences)

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12 pages, 956 KiB

Open AccessReview

A Precision Strategy to Cure Renal Cell Carcinoma by Targeting Transglutaminase 2

by Soo-Youl Kim and Jeffrey W. Keillor

Int. J. Mol. Sci. 2020, 21(7), 2493; https://doi.org/10.3390/ijms21072493 - 03 Apr 2020

Cited by 5 | Viewed by 3205

Abstract

In a recent report, no significance of transglutaminase 2 (TGase 2) was noted in the analyses of expression differences between normal and clear cell renal cell carcinoma (ccRCC), although we found that knock down of TGase 2 induced significant p53-mediated cell death in [...] Read more.

In a recent report, no significance of transglutaminase 2 (TGase 2) was noted in the analyses of expression differences between normal and clear cell renal cell carcinoma (ccRCC), although we found that knock down of TGase 2 induced significant p53-mediated cell death in ccRCC. Generally, to find effective therapeutic targets, we need to identify targets that belong specifically to a cancer phenotype that can be differentiated from a normal phenotype. Here, we offer precise reasons why TGase 2 may be the first therapeutic target for ccRCC, according to several lines of evidence. TGase 2 is negatively regulated by von Hippel-Lindau tumor suppressor protein (pVHL) and positively regulated by hypoxia-inducible factor 1-α (HIF-1α) in renal cell carcinoma (RCC). Therefore, most of ccRCC presents high level expression of TGase 2 because over 90% of ccRCC showed VHL inactivity through mutation and methylation. Cell death, angiogenesis and drug resistance were specifically regulated by TGase 2 through p53 depletion in ccRCC because over 90% of ccRCC express wild type p53, which is a cell death inducer as well as a HIF-1α suppressor. Although there have been no detailed studies of the physiological role of TGase 2 in multi-omics analyses of ccRCC, a life-long study of the physiological roles of TGase 2 led to the discovery of the first target as well as the first therapeutic treatment for ccRCC in the clinical field. Full article

(This article belongs to the Special Issue The World of Transglutaminases: From Basic Biological and Medical Research to Applied Sciences)

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12 pages, 23915 KiB

Open AccessReview

Structures of Human Transglutaminase 2: Finding Clues for Interference in Cross-linking Mediated Activity

by Gi Eob Kim and Hyun Ho Park

Int. J. Mol. Sci. 2020, 21(6), 2225; https://doi.org/10.3390/ijms21062225 - 23 Mar 2020

Cited by 9 | Viewed by 3520

Abstract

Human transglutaminase 2 (TGase2) has various functions, including roles in various cellular processes such as apoptosis, development, differentiation, wound healing, and angiogenesis, and is linked to many diseases such as cancer. Although TGase2 has been considered an optimized drug target for the treatment [...] Read more.

Human transglutaminase 2 (TGase2) has various functions, including roles in various cellular processes such as apoptosis, development, differentiation, wound healing, and angiogenesis, and is linked to many diseases such as cancer. Although TGase2 has been considered an optimized drug target for the treatment of cancer, fibrosis, and neurodegenerative disorders, it has been difficult to generate TGase2-targeted drugs for clinical use because of the relatively flat and broad active site on TGase2. To design more specific and powerful inhibitors, detailed structural information about TGase2 complexed with various effector and inhibitor molecules is required. In this review, we summarized the current structural studies on TGase2, which will aid in designing drugs that can overcome the aforementioned limitations. Full article

(This article belongs to the Special Issue The World of Transglutaminases: From Basic Biological and Medical Research to Applied Sciences)

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13 pages, 883 KiB

Open AccessReview

Processed Food Additive Microbial Transglutaminase and Its Cross-Linked Gliadin Complexes Are Potential Public Health Concerns in Celiac Disease

by Aaron Lerner and Torsten Matthias

Int. J. Mol. Sci. 2020, 21(3), 1127; https://doi.org/10.3390/ijms21031127 - 08 Feb 2020

Cited by 18 | Viewed by 5920

Abstract

Microbial transglutaminase (mTG) is a survival factor for microbes, but yeasts, fungi, and plants also produce transglutaminase. mTG is a cross-linker that is heavily consumed as a protein glue in multiple processed food industries. According to the manufacturers’ claims, microbial transglutaminase and its [...] Read more.

Microbial transglutaminase (mTG) is a survival factor for microbes, but yeasts, fungi, and plants also produce transglutaminase. mTG is a cross-linker that is heavily consumed as a protein glue in multiple processed food industries. According to the manufacturers’ claims, microbial transglutaminase and its cross-linked products are safe, i.e., nonallergenic, nonimmunogenic, and nonpathogenic. The regulatory authorities declare it as “generally recognized as safe” for public users. However, scientific observations are accumulating concerning its undesirable effects on human health. Functionally, mTG imitates its family member, tissue transglutaminase, which is the autoantigen of celiac disease. Both these transglutaminases mediate cross-linked complexes, which are immunogenic in celiac patients. The enzyme enhances intestinal permeability, suppresses mechanical (mucus) and immunological (anti phagocytic) enteric protective barriers, stimulates luminal bacterial growth, and augments the uptake of gliadin peptide. mTG and gliadin molecules are cotranscytosed through the enterocytes and deposited subepithelially. Moreover, mucosal dendritic cell surface transglutaminase induces gliadin endocytosis, and the enzyme-treated wheat products are immunoreactive in CD patients. The present review summarizes and updates the potentially detrimental effects of mTG, aiming to stimulate scientific and regulatory debates on its safety, to protect the public from the enzyme’s unwanted effects. Full article

(This article belongs to the Special Issue The World of Transglutaminases: From Basic Biological and Medical Research to Applied Sciences)

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