Role of Transglutaminase 2 in Cell Death, Survival, and Fibrosis

Overview

Journal Cells

Publisher MDPI

Specialties Biochemistry
Biophysics
Cell Biology
Molecular Biology

Date 2021 Aug 7

PMID 34360011

Citations 32

Authors

Hideki Tatsukawa

Kiyotaka Hitomi

Affiliations

Soon will be listed here.

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 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 Ca or other factors, TG2 adopts a Ca-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.

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References

Chen C, Wu C, Lai Y, Lee W, Chen H, Chen R . NF-kappaB-activated tissue transglutaminase is involved in ethanol-induced hepatic injury and the possible role of propolis in preventing fibrogenesis. Toxicology. 2008; 246(2-3):148-57. DOI: 10.1016/j.tox.2008.01.009. View

Ghanta K, Pakala S, Reddy S, Li D, Nair S, Kumar R . MTA1 coregulation of transglutaminase 2 expression and function during inflammatory response. J Biol Chem. 2010; 286(9):7132-8. PMC: 3044970. DOI: 10.1074/jbc.M110.199273. View

Boros S, Ahrman E, Wunderink L, Kamps B, de Jong W, Boelens W . Site-specific transamidation and deamidation of the small heat-shock protein Hsp20 by tissue transglutaminase. Proteins. 2005; 62(4):1044-52. DOI: 10.1002/prot.20837. View

Jang G, Jeon J, Cho S, Shin D, Kim C, Jeong E . Transglutaminase 2 suppresses apoptosis by modulating caspase 3 and NF-kappaB activity in hypoxic tumor cells. Oncogene. 2009; 29(3):356-67. DOI: 10.1038/onc.2009.342. View

Junn E, Ronchetti R, Quezado M, Kim S, Mouradian M . Tissue transglutaminase-induced aggregation of alpha-synuclein: Implications for Lewy body formation in Parkinson's disease and dementia with Lewy bodies. Proc Natl Acad Sci U S A. 2003; 100(4):2047-52. PMC: 149956. DOI: 10.1073/pnas.0438021100. View

Fesus L . Biochemical events in naturally occurring forms of cell death. FEBS Lett. 1993; 328(1-2):1-5. DOI: 10.1016/0014-5793(93)80952-q. View

Keillor J, Clouthier C, Apperley K, Akbar A, Mulani A . Acyl transfer mechanisms of tissue transglutaminase. Bioorg Chem. 2014; 57:186-197. DOI: 10.1016/j.bioorg.2014.06.003. View

Occhigrossi L, Rossin F, DEletto M, Farrace M, Ciccosanti F, Petrone L . Transglutaminase 2 Regulates Innate Immunity by Modulating the STING/TBK1/IRF3 Axis. J Immunol. 2021; 206(10):2420-2429. DOI: 10.4049/jimmunol.2001122. View

Huh C, Factor V, Sanchez A, Uchida K, Conner E, Thorgeirsson S . Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair. Proc Natl Acad Sci U S A. 2004; 101(13):4477-82. PMC: 384772. DOI: 10.1073/pnas.0306068101. View

10.

Lai T, Bielawska A, Peoples K, Hannun Y, Greenberg C . Sphingosylphosphocholine reduces the calcium ion requirement for activating tissue transglutaminase. J Biol Chem. 1997; 272(26):16295-300. DOI: 10.1074/jbc.272.26.16295. View

11.

Curro M, Condello S, Caccamo D, Ferlazzo N, Parisi G, Ientile R . Homocysteine-induced toxicity increases TG2 expression in Neuro2a cells. Amino Acids. 2008; 36(4):725-30. DOI: 10.1007/s00726-008-0122-x. View

12.

Fesus L, Szondy Z . Transglutaminase 2 in the balance of cell death and survival. FEBS Lett. 2005; 579(15):3297-302. DOI: 10.1016/j.febslet.2005.03.063. View

13.

Begg G, Carrington L, Stokes P, Matthews J, Wouters M, Husain A . Mechanism of allosteric regulation of transglutaminase 2 by GTP. Proc Natl Acad Sci U S A. 2006; 103(52):19683-8. PMC: 1750866. DOI: 10.1073/pnas.0609283103. View

14.

Tatsukawa H, Tani Y, Otsu R, Nakagawa H, Hitomi K . Global identification and analysis of isozyme-specific possible substrates crosslinked by transglutaminases using substrate peptides in mouse liver fibrosis. Sci Rep. 2017; 7:45049. PMC: 5361200. DOI: 10.1038/srep45049. View

15.

Iismaa S, Mearns B, Lorand L, Graham R . Transglutaminases and disease: lessons from genetically engineered mouse models and inherited disorders. Physiol Rev. 2009; 89(3):991-1023. DOI: 10.1152/physrev.00044.2008. View

16.

Tucholski J, Roth K, Johnson G . Tissue transglutaminase overexpression in the brain potentiates calcium-induced hippocampal damage. J Neurochem. 2006; 97(2):582-94. DOI: 10.1111/j.1471-4159.2006.03780.x. View

17.

Kleman J, Aeschlimann D, Paulsson M, van Der Rest M . Transglutaminase-catalyzed cross-linking of fibrils of collagen V/XI in A204 rhabdomyosarcoma cells. Biochemistry. 1995; 34(42):13768-75. DOI: 10.1021/bi00042a007. View

18.

Mishra S, Murphy L . Tissue transglutaminase has intrinsic kinase activity: identification of transglutaminase 2 as an insulin-like growth factor-binding protein-3 kinase. J Biol Chem. 2004; 279(23):23863-8. DOI: 10.1074/jbc.M311919200. View

19.

Kaartinen M, Pirhonen A, Linnala-Kankkunen A, Maenpaa P . Transglutaminase-catalyzed cross-linking of osteopontin is inhibited by osteocalcin. J Biol Chem. 1997; 272(36):22736-41. DOI: 10.1074/jbc.272.36.22736. View

20.

Collighan R, Griffin M . Transglutaminase 2 cross-linking of matrix proteins: biological significance and medical applications. Amino Acids. 2008; 36(4):659-70. DOI: 10.1007/s00726-008-0190-y. View