cytosolic guanine nucledotide binding deficient form of transglutaminase 2 (r580a) potentiates cell death in oxygen glucose deprivation胞质鸟嘌呤nucledotide绑定缺乏形式的转谷氨酰胺酶2(r580a)强化细胞死亡在氧葡萄糖剥夺.pdfVIP

Cytosolic Guanine Nucledotide Binding Deficient Form of Transglutaminase 2 (R580a) Potentiates Cell Death in Oxygen Glucose Deprivation 1 2 1,3 Gozde Colak , Jeffrey W. Keillor , Gail V. W. Johnson * ´ ´ ´ 1 Department of Pharmacology and Physiology, University of Rochester, Rochester, New York, United States of America, 2 Departement de Chimie, Universite de Montreal, ´ Montreal, Canada, 3 Department of Anesthesiology, University of Rochester, Rochester, New York, United States of America Abstract Transglutaminase 2 (TG2) is a hypoxia-responsive protein that is a calcium-activated transamidating enzyme, a GTPase and a scaffolding/linker protein. Upon activation TG2 undergoes a large conformational change, which likely affects not only its enzymatic activities but its non-catalytic functions as well. The focus of this study was on the role of transamidating activity, conformation and localization of TG2 in ischemic cell death. Cells expressing a GTP binding deficient form of TG2 (TG2- R580A) with high basal transamidation activity and a more extended conformation showed significantly increased cell death in response to oxygen-glucose deprivation; however, targeting TG2-R580A to the nucleus abrogated its detrimental role in oxygen-glucose deprivation. Treatment of cells expressing wild type TG2, TG2-C277S (a transamidating inactive mutant) and TG2-R580A with Cp4d, a reversible TG2 inhibitor, did not affect cell death in response to oxygen-glucose deprivation. These findings indicate that the pro-cell death effects of TG2 are dependent on its localization to the