Role of Transglutaminase 2 in Cell Death, Survival, and Fibrosis.
Tatsukawa Hideki,Hitomi Kiyotaka
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.
Serotonylation: Serotonin Signaling and Epigenetics.
Frontiers in molecular neuroscience
Serotonylation, the covalent linkage of serotonin to proteins has been discovered more than 60 years ago but only recently the mechanisms and first functions have been elucidated. It has been found that transglutaminases (TG) such as TG2 and the blood coagulation factor XIIIa are the enzymes which catalyze the linkage of serotonin and other monoamines to distinct glutamine (Gln) residues of target proteins. The first target proteins, small G-proteins and extracellular matrix constituents, were found in platelets and are pivotally involved in platelet aggregation and the formation of thrombi. The serotonylation of the same proteins is also involved in insulin secretion and in the proliferation of pulmonary vascular smooth muscle cells and thereby in the pathogenesis of pulmonary arterial hypertension (PAH). Recently histones have been described as targets of serotonylation opening the area of transcriptional control to this posttranslational protein modification. Future studies will certainly reveal further target proteins, signaling pathways, cellular processes, and diseases, in which serotonylation or, more general, monoaminylation is important.