Faculty Profiles - TATSUKAWA Hideki

Papers - TATSUKAWA Hideki

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Tissue transglutaminase exacerbates renal fibrosis via alternative activation of monocyte-derived macrophages Reviewed International journal

Yoshiki Shinoda, Hideki Tatsukawa, Atsushi Yonaga, Ryosuke Wakita, Taishu Takeuchi, Tokuji Tsuji, Miyako Tanaka, Takayoshi Suganami, Kiyotaka Hitomi

Cell Death & Disease Vol. 14 ( 2 ) page： 136 - 136 2023.3

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

Abstract

Macrophages are important components in modulating homeostatic and inflammatory responses and are generally categorized into two broad but distinct subsets: classical activated (M1) and alternatively activated (M2) depending on the microenvironment. Fibrosis is a chronic inflammatory disease exacerbated by M2 macrophages, although the detailed mechanism by which M2 macrophage polarization is regulated remains unclear. These polarization mechanisms have little in common between mice and humans, making it difficult to adapt research results obtained in mice to human diseases. Tissue transglutaminase (TG2) is a known marker common to mouse and human M2 macrophages and is a multifunctional enzyme responsible for crosslinking reactions. Here we sought to identify the role of TG2 in macrophage polarization and fibrosis. In IL-4-treated macrophages derived from mouse bone marrow and human monocyte cells, the expression of TG2 was increased with enhancement of M2 macrophage markers, whereas knockout or inhibitor treatment of TG2 markedly suppressed M2 macrophage polarization. In the renal fibrosis model, accumulation of M2 macrophages in fibrotic kidney was significantly reduced in TG2 knockout or inhibitor-administrated mice, along with the resolution of fibrosis. Bone marrow transplantation using TG2-knockout mice revealed that TG2 is involved in M2 polarization of infiltrating macrophages derived from circulating monocytes and exacerbates renal fibrosis. Furthermore, the suppression of renal fibrosis in TG2-knockout mice was abolished by transplantation of wild-type bone marrow or by renal subcapsular injection of IL4-treated macrophages derived from bone marrow of wild-type, but not TG2 knockout. Transcriptome analysis of downstream targets involved in M2 macrophages polarization revealed that ALOX15 expression was enhanced by TG2 activation and promoted M2 macrophage polarization. Furthermore, the increase in the abundance of ALOX15-expressing macrophages in fibrotic kidney was dramatically suppressed in TG2-knockout mice. These findings demonstrated that TG2 activity exacerbates renal fibrosis by polarization of M2 macrophages from monocytes via ALOX15.

DOI： 10.1038/s41419-023-05622-5

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PubMed

Other Link： https://www.nature.com/articles/s41419-023-05622-5

Spatially Resolved Identification of Transglutaminase Substrates by Proteomics in Pulmonary Fibrosis. Reviewed International journal

Taishu Takeuchi, Hideki Tatsukawa, Yoshiki Shinoda, Keiko Kuwata, Miyuki Nishiga, Hiroshi Takahashi, Naoki Hase, Kiyotaka Hitomi

American journal of respiratory cell and molecular biology Vol. 65 ( 3 ) page： 319 - 330 2021.9

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

Idiopathic pulmonary fibrosis (IPF) is characterized by the invariably progressive deposition of fibrotic tissue in the lungs and overall poor prognosis. TG2 (transglutaminase 2) is an enzyme that crosslinks glutamine and lysine residues and is involved in IPF pathogenesis. Despite the accumulating evidence implicating TG2 as a critical enzyme, the causative function and direct target of TG2 relating to this pathogenesis remain unelucidated. Here, we clarified the distributions of TG2 protein/activity and conducted quantitative proteomics analyses of possible substrates crosslinked by TG2 on unfixed lung sections in a mouse pulmonary fibrosis model. We identified 126 possible substrates as markedly TG2-dependently increased in fibrotic lung. Gene ontology analysis revealed that these identified proteins were mostly enriched in the lipid metabolic process, immune system process, and protein transport. In addition, these proteins were enriched in 21 pathways, including phagosome, lipid metabolism, several immune responses, and protein processing in endoplasmic reticulum. Furthermore, the network analyses screened out the six clusters and top 20 hub proteins with higher scores, which are related to endoplasmic reticulum stress and peroxisome proliferator-activated receptor signals. Several enriched pathways and categories were identified, some of which were the same terms based on transcription analysis in IPF. Our results provide novel pathological molecular networks driven by protein crosslinking via TG2, which can lead to the development of new therapeutic targets for IPF.

DOI： 10.1165/rcmb.2021-0012OC

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PubMed

Isozyme-specific comprehensive characterization of transglutaminase-crosslinked substrates in kidney fibrosis. Reviewed International journal

Hideki Tatsukawa, Risa Otsu, Yuji Tani, Ryosuke Wakita, Kiyotaka Hitomi

Scientific reports Vol. 8 ( 1 ) page： 7306 - 7306 2018.5

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

Chronic kidney disease is characterized by prolonged decline in renal function, excessive accumulation of ECM, and progressive tissue fibrosis. Transglutaminase (TG) is a crosslinking enzyme that catalyzes the formation of covalent bonds between glutamine and lysine residues, and is involved in the induction of renal fibrosis via the stabilization of ECM and the activation of TGF-β1. Despite the accumulating evidences indicating that TG2 is a key enzyme in fibrosis, genetic knockout of TG2 reduced by only 50% the elevated protein crosslinking and fibrous protein in renal fibrosis model, whereas treatment with TG inhibitor almost completely reduced these levels. Here, we also clarified the distributions of TG isozymes and their in situ activities and identified the isozyme-specific crosslinked substrates for both TG1 and TG2 in fibrotic kidney. We found that TG1 activity was markedly enhanced in renal tubular epithelium and interstitial areas, whereas TG2 activity increased only in the extracellular space. In total, 47 and 67 possible candidates were identified as TG1 and TG2 substrates, respectively, only in fibrotic kidney. Among them, several possible substrates related to renal disease and fibrosis were identified. These findings provide novel insights into the mechanisms of renal fibrosis through the targeting of isozyme-specific TG substrates.

DOI： 10.1038/s41598-018-25674-4

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PubMed

Global identification and analysis of isozyme-specific possible substrates crosslinked by transglutaminases using substrate peptides in mouse liver fibrosis. Reviewed International journal

Hideki Tatsukawa, Yuji Tani, Risa Otsu, Haruka Nakagawa, Kiyotaka Hitomi

Scientific reports Vol. 7 page： 45049 - 45049 2017.3

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

The transglutaminase (TG) family comprises eight isozymes that form the isopeptide bonds between glutamine and lysine residues and contribute to the fibrotic diseases via crosslinking-mediated stabilization of ECM and the activation of TGF-β in several tissues. However, despite a growing body of evidence implicating TG2 as a key enzyme in fibrosis, the causative role of TG2 and the involvement of the other isozymes have not yet been fully elucidated. Therefore, here we clarified the distributions of TG isozymes and their in situ activities and identified the isozyme-specific possible substrates for both TG1 and TG2 using their substrate peptides in mouse fibrotic liver. We found that TG1 activity was markedly enhanced intracellularly over a widespread area, whereas TG2 activity increased in the extracellular space. In total, 43 and 42 possible substrates were identified for TG1 and TG2, respectively, as involved in chromatin organization and cellular component morphogenesis. These included keratin 18, a biomarker for hepatic injury, which was accumulated in the fibrotic liver and showed the partly similar distribution with TG1 activity. These findings suggest that TG1 activity may be involved in the functional modification of intracellular proteins, whereas TG2 activity contributes to the stabilization of extracellular proteins during liver fibrosis.

DOI： 10.1038/srep45049

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PubMed

Potential activity of chicken amniotic fluid in epidermal development by promoting keratinocyte differentiation. Reviewed

Tokuji Tsuji, Ryo Onogawa, Hideki Tatsukawa, Atsushi Murai, Kiyotaka Hitomi

Archives of Biochemistry and Biophysics Vol. 768 page： 110365 - 110365 2025.2

Transglutaminase 1: Emerging Functions beyond Skin Reviewed International coauthorship

Samani, SE; Tatsukawa, H; Hitomi, K; Kaartinen, MT

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol. 25 ( 19 ) 2024.10

Analysis on promotive effect of rocking culture on keratinocyte differentiation in 3-dimensional reconstitution human epidermis Reviewed

Mayuko Endo, Hirofumi Teshima, Kojin Kitadani, Kobayashi Minoru, Tokuji Tsuji, Hideki Tatsukawa, Hiroshi Harada, Kiyotaka Hitomi

Bioscience, Biotechnology, and Biochemistry Vol. 88 ( 8 ) page： 932 - 940 2024.6

Language：English Publishing type：Research paper (scientific journal) Publisher：Oxford University Press (OUP)

ABSTRACT

A 3-dimensional culture system of keratinocytes achieves cornification as a terminal differentiation that can mimic the formation of stratified epidermis. At the onset of keratinocyte differentiation, air-exposure treatment is essential for promotion. We have previously reported that the stimulation of differentiation is accompanied by downregulation of the transcriptional activity of the hypoxia-inducible factor (HIF) and also found that rocking treatment of cultured keratinocytes in the submerged condition restored their differentiation. A comparative study of cultured keratinocytes with and without rocking was then carried out to investigate the characteristics of the recovered differentiation by morphological and biochemical analyses. In addition, transcriptome analysis revealed the expected similar pattern between air-exposed and rocking cultures, including HIF-regulating transcripts. Furthermore, the promotive effect of rocking treatment was impaired under hypoxic culture conditions (1% O2). We showed that the restored promotion of differentiation by rocking culture is mainly due to the abrogation of transcriptional events by hypoxia.

DOI： 10.1093/bbb/zbae070

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PubMed

Novel function of transglutaminase 2 in extracellular histone-induced acute lung injury. International journal

Tomohiro Mizuno, Fumihiko Nagano, Yoshimasa Ito, Hideki Tatsukawa, Yoshiki Shinoda, Taishu Takeuchi, Kazuo Takahashi, Naotake Tsuboi, Tadashi Nagamatsu, Shuhei Yamada, Shoichi Maruyama, Kiyotaka Hitomi

Biochemical and biophysical research communications Vol. 678 page： 179 - 185 2023.10

Language：English Publishing type：Research paper (scientific journal)

Extracellular histones induce endothelial damage, resulting in lung haemorrhage; however, the underlying mechanism remains unclear. Factor XIII, as a Ca2+-dependent cross-linking enzyme in blood, mediates fibrin deposition. As another isozyme, transglutaminase 2 (TG2) has a catalytic activity distributing in most tissues. Herein, we investigated whether TG2 promotes fibrin deposition and mediates the adhesion of platelets to ECs in histone-induced acute lung injury (ALI). We evaluated the lung histology and the adhesion of platelets to endothelial cells (ECs) after injecting histones to wild-type (WT) C57BL/6J and TG2 knockout (TG2-/-) mice, and administered a TG2 inhibitor (NC9) to WT mice. Pulmonary haemorrhage was more severe in TG2-/- mice than that in WT mice. The area of fibrin deposition and the proportion of CD41+CD31+ cells were lower in TG2-/- mice than in WT mice. Pre-treatment of NC9 decreased the area of fibrin deposition and the proportion of CD41+CD31+ cells in WT mice. These results suggest that TG2 prevents from pulmonary haemorrhage in ALI by promoting the adhesion of platelets to ECs and the fibrin deposition.

DOI： 10.1016/j.bbrc.2023.08.051

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Development of peptide-based biosensors for detecting cross-linking and deamidation activities of transglutaminases. Reviewed International journal

Hideki Tatsukawa, Ruriko Aoyama, Kiyotaka Hitomi

Amino acids Vol. 55 ( 6 ) page： 807 - 819 2023.6

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

Transglutaminases (TGs) are a protein family that catalyzes isopeptide bond formation between glutamine and lysine residues of various proteins. There are eight TG isozymes in humans, and each is involved in diverse biological phenomena due to their characteristic distribution. Abnormal activity of TG1 and TG2, which are major TG isozymes, is believed to cause various diseases, such as ichthyosis and celiac disease. To elucidate TGs' mechanisms of action and develop new therapeutic strategies, it is essential to develop bioprobes that can specifically examine the activity of each TG isozyme, which has not been sufficiently studied. We previously have identified several substrate peptide sequences containing Gln residues for each isozyme and developed a method to detect isozyme-specific activities by incorporating a labeled substrate peptide into lysine residues of proteins. We prepared the fluorescein isothiocyanate (FITC)-labeled Gln substrate peptide (FITC-K5 and FITC-T26) and Rhodamine B-labeled Lys substrate peptide (RhoB-Kpep). Each TG reaction specifically cross-linked these probe pairs, and the proximity of FITC and Rhodamine B significantly decreased the fluorescence intensity of FITC depending on the concentration and reaction time of each TG. In this study, we developed a peptide-based biosensor that quickly and easily measures TG isozyme-specific activity. This probe is expected to be helpful in elucidating TG's physiological and pathological functions and in developing compounds that modulate TG activity.

DOI： 10.1007/s00726-023-03272-7

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PubMed

Inhibition of Transglutaminase 2 Reduces Peritoneal Injury in a Chlorhexidine-Induced Peritoneal Fibrosis Model. Reviewed International journal

Shunnosuke Kunoki, Hideki Tatsukawa, Yukinao Sakai, Hiroshi Kinashi, Tetsuyoshi Kariya, Yasuhiro Suzuki, Masashi Mizuno, Makoto Yamaguchi, Hiroyuki Sasakura, Masashi Ikeno, Kosei Takeuchi, Takuji Ishimoto, Kiyotaka Hitomi, Yasuhiko Ito

Laboratory investigation; a journal of technical methods and pathology Vol. 103 ( 4 ) page： 100050 - 100050 2023.4

Language：English Publishing type：Research paper (scientific journal)

Long-term peritoneal dialysis (PD) is often associated with peritoneal dysfunction leading to withdrawal from PD. The characteristic pathologic features of peritoneal dysfunction are widely attributed to peritoneal fibrosis and angiogenesis. The detailed mechanisms remain unclear, and treatment targets in clinical settings have yet to be identified. We investigated transglutaminase 2 (TG2) as a possible novel therapeutic target for peritoneal injury. TG2 and fibrosis, inflammation, and angiogenesis were investigated in a chlorhexidine gluconate (CG)-induced model of peritoneal inflammation and fibrosis, representing a noninfectious model of PD-related peritonitis. Transforming growth factor (TGF)-β type I receptor (TGFβR-I) inhibitor and TG2-knockout mice were used for TGF-β and TG2 inhibition studies, respectively. Double immunostaining was performed to identify cells expressing TG2 and endothelial-mesenchymal transition (EndMT). In the rat CG model of peritoneal fibrosis, in situ TG2 activity and protein expression increased during the development of peritoneal fibrosis, as well as increases in peritoneal thickness and numbers of blood vessels and macrophages. TGFβR-I inhibitor suppressed TG2 activity and protein expression, as well as peritoneal fibrosis and angiogenesis. TGF-β1 expression, peritoneal fibrosis, and angiogenesis were suppressed in TG2-knockout mice. TG2 activity was detected by α-smooth muscle actin-positive myofibroblasts, CD31-positive endothelial cells, and ED-1-positive macrophages. CD31-positive endothelial cells in the CG model were α-smooth muscle actin-positive, vimentin-positive, and vascular endothelial-cadherin-negative, suggesting EndMT. In the CG model, EndMT was suppressed in TG2-knockout mice. TG2 was involved in the interactive regulation of TGF-β. As inhibition of TG2 reduced peritoneal fibrosis, angiogenesis, and inflammation associated with TGF-β and vascular endothelial growth factor-A suppression, TG2 may provide a new therapeutic target for ameliorating peritoneal injuries in PD.

DOI： 10.1016/j.labinv.2022.100050

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Involvement of hypoxia inducible factor activity in inevitable air-exposure treatment upon differentiation in a three-dimensional keratinocyte culture. Reviewed International journal

Teshima H, Endo M, Furuyama Y, Takama H, Tsuji T, Tatsukawa H, Akiyama M, Hitomi K

FEBS J. Vol. 290 ( 8 ) page： 2049 - 2063 2023.4

Language：English Publishing type：Research paper (scientific journal) Publisher：Wiley

Formation of the human skin epidermis can be reproduced by a three-dimensional (3D) keratinocyte culture system, in which air-exposure is inevitable upon initiation of differentiation. In the continuous submerged culture without air-exposure, even with a differentiation-compatible medium, several keratinocyte-specific proteins were not induced resulting in the formation of aberrant epidermal layers. To clarify the mechanism by which air-exposure promotes keratinocyte differentiation, we performed a comparative analysis on biological properties between submerged and air-liquid interphase culture systems. By transcriptomic analysis, hypoxia-inducible factor (HIF)-related genes appeared to significantly change in these cultured cells. In submerged culture, the transcriptional activity of HIF on its canonical response element was enhanced, while air-exposure treatment drastically reduced the transcriptional activity despite the high HIF protein level. Regulating HIF activity through reagents and genetic manipulation revealed that the reduced but retained HIF-transcriptional activity was essentially involved in differentiation. Furthermore, we showed, for the first time, that artificial supplementation of oxygen in the submerged culture system could restore keratinocyte differentiation as observed in the air-exposed culture. Thus, we mechanistically evaluated how HIF regulates the air-exposure-dependent differentiation of keratinocytes in a 3D culture system.

DOI： 10.1111/febs.16707

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PubMed

Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/febs.16707

Biochemical characterization of medaka (Oryzias latipes) fibrinogen gamma and its gene disruption resulting in anemia as a model fish. Reviewed International journal

Qi Meng, Yuko Watanabe, Hideki Tatsukawa, Hisashi Hashimoto, Kiyotaka Hitomi

Journal of biochemistry Vol. 172 ( 5 ) page： 293 - 302 2022.10

Language：English Publishing type：Research paper (scientific journal)

At the final stages of blood coagulation, fibrinogen is processed into insoluble fibrin by thrombin resulting in fibril-like structure formation. Via further cross-linking reactions between the fibrin gamma subunit by the catalytic action of blood transglutaminase (Factor XIII), this molecule gains further physical stability. Meanwhile, since fibrinogen is expressed in various cells and tissues, this molecule can exhibit other functions apart from its role in blood coagulation. To create a system studying on aberrant coagulation and investigate the physiological functions, using a model fish medaka (Oryzias latipes), we established gene-deficient mutants of fibrinogen gamma subunit protein in parallel with its biochemical analysis, such as tissue distribution pattern and substrate properties. By genetic deletion via genome editing, two distinct mutants displayed retardation of blood coagulation. The mutants showed lower hematocrit with aberrant erythrocyte maturation, which indicates that fibrin deficiency caused severe anemia, and also appeared as a model for investigation of the fibrin function.

DOI： 10.1093/jb/mvac065

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PubMed

臓器の線維化を誘導するタンパク質架橋酵素の網羅的な分子標的解析 Invited

辰川英樹, 人見清隆

バイオサイエンスとインダストリー Vol. 80 ( 2 ) page： 1 - 5 2022.3

Investigation of mouse amniotic fluid for stimulating ability of keratinocyte differentiation depending on the fetal stage. International journal

Miki Kuribayashi, Yusuke Kawaguchi, Hirofumi Teshima, Hisateru Yamaguchi, Hideki Tatsukawa, Kiyotaka Hitomi

Archives of biochemistry and biophysics Vol. 711 page： 109003 - 109003 2021.10

Language：English Publishing type：Research paper (scientific journal)

During fetal development, the barrier function of the fetal skin is developed under specific conditions for epidermis formation. In keratinocyte differentiation, the well-orchestrated production and modification of various structural proteins are induced. We assessed the epidermal barrier function in different fetal stages by evaluating the enzymatic activity of cross-linking proteins, transglutaminases, and the permeation of fluorescence dye in the stained epidermal sections. During days 15.5-17.5 in gestation, the enzymatic activities in the epidermis appeared to increase significantly; meanwhile, dye permeation was substantially decreased, suggesting the formation of a protective barrier. For the fetal epidermis formation in the earlier stage, unclarified stimulating factors in the amniotic fluid (AF) are possible to promote barrier function by stimulating keratinocyte differentiation. Thus, we performed proteomic spectrometric (MS) analysis on the components in the AF at different fetal stages. Also, we investigated the promotive ability of the components using a cultured keratinocyte differentiation system. According to the MS analysis, the AF components appeared to exhibit stage-specific variations, where possible unique functions have been identified. We also found that adding the AF from each stage to the medium for cultured keratinocytes specifically enhanced the levels of the differentiation markers. These results provide information on the possible role of AF that contains regulatory factors on keratinocyte differentiation.

DOI： 10.1016/j.abb.2021.109003

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Role of Transglutaminase 2 in Cell Death, Survival, and Fibrosis. Invited Reviewed International journal

Hideki Tatsukawa, Kiyotaka Hitomi

Cells Vol. 10 ( 7 ) 2021.7

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.3390/cells10071842

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PubMed

タンパク質架橋化酵素トランスグルタミナーゼの糸球体炎症進展への役割解明

伊藤辰将, 辰川英樹, 梅田良祐, 横江優貴, 高橋和男, 湯澤由紀夫, 人見清隆, 坪井直毅

日本腎臓学会誌 Vol. 63 ( 4 ) page： 519 - 519 2021.6

タンパク質架橋化酵素トランスグルタミナーゼの糸球体炎症進展への役割解明

伊藤辰将, 辰川英樹, 梅田良祐, 横江優貴, 高橋和男, 湯澤由紀夫, 人見清隆, 坪井直毅

日本腎臓学会誌 Vol. 63 ( 4 ) page： 519 - 519 2021.6

Thrombin-deficient mutant of medaka, a model fish, displays serious retardation in blood coagulation. Reviewed

doi: 10.1093/bbb/zbaa098.

Biosci Biotechnol Biochem 2021.2

Thrombin-deficient mutant of medaka, a model fish, displays serious retardation in blood coagulation. International journal

Yuko Watanabe, Rina Oguri, Risa Suzuki, Qi Meng, Yuta Ishikawa, Hideki Tatsukawa, Hisashi Hashimoto, Kiyotaka Hitomi

Bioscience, biotechnology, and biochemistry Vol. 85 ( 4 ) page： 824 - 833 2021

Language：English Publishing type：Research paper (scientific journal)

At the last stage of the blood coagulation cascade, thrombin plays a central role in the processing of fibrinogen for the polymerization and in the additional activation of Factor XIII for the stable cross-linking of fibrin. In addition, thrombin carries out possible multiple roles via processing or interaction with various functional proteins. Several studies conducted in order to elucidate additional physiological significance are ongoing. To clarify further significance of thrombin and to establish an associated disease model, we characterized the orthologue gene for medaka (Oryzias latipes), a research model fish. Tissue distribution of medaka prothrombin has been immunotechnically analyzed. Furthermore, thrombin-deficient medaka mutants were viably established by utilizing a genome-editing method. The established gene-deficient mutants exhibited retarded blood coagulation even in the heterozygous fish. Taking advantage of their ease of handling, this specific model is useful for further investigation in medical research areas on human coagulation diseases.

DOI： 10.1093/bbb/zbaa098

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Identification and characterization of substrates crosslinked by transglutaminases in liver and kidney fibrosis. Reviewed International journal

Hideki Tatsukawa, Taishu Takeuchi, Yoshiki Shinoda, Kiyotaka Hitomi

Analytical biochemistry Vol. 604 page： 113629 - 113629 2020.9

Authorship：Lead author,　Corresponding author Language：Japanese Publishing type：Research paper (scientific journal)

The transglutaminase (TGase) family consists of eight isozymes that catalyze Ca2+-dependent crosslink formation between glutamine and lysine residues of proteins. In the pathogenesis of various chronic diseases, among the TGase isozymes, TG2 in particular is upregulated and contributes to a critical role in fibrosis development and progression via the stabilization of extracellular matrix proteins and activation of TGF-β. Although TG2 has been considered a key enzyme in fibrosis, the causative role of TG2 and involvement of other isozymes remain unclear. We have recently developed a comprehensive analysis method targeting the isozyme-specific substrates of TGase in liver and kidney fibrosis. In this review article, we introduce a previously developed method for determining the activity and tissue distribution of TGase and for the detecting and identification of TGase substrates in an isozyme-specific manner. Using our comprehensive analysis method, we newly characterized the overlapping profile data regarding potential substrates of TG1 and TG2 that have been identified in liver and kidney fibrosis to date. Our results obtained by comparing the specificity and similarity of potential TGase substrates between different tissue fibrosis models provide a deeper understanding regarding the specific and common pathways in disease pathogenesis and progression.

DOI： 10.1016/j.ab.2020.113629

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Papers - TATSUKAWA Hideki