chop mediates endoplasmic reticulum stress-induced apoptosis in gimap5-deficient t cells切调节内质网应激在gimap5-deficient t细胞凋亡.pdfVIP

CHOP Mediates Endoplasmic Reticulum Stress-Induced Apoptosis in Gimap5-Deficient T Cells 1 1 1 1 1 Steven C. Pino , Bryan O’Sullivan-Murphy , Erich A. Lidstone , Chaoxing Yang , Kathryn L. Lipson , 1 1 1 1 1,2 1,2 Agata Jurczyk , Philip diIorio , Michael A. Brehm , John P. Mordes , Dale L. Greiner , Aldo A. Rossini , Rita Bortell1* 1 Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America, 2 Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America Abstract Gimap5 (GTPase of the immunity-associated protein 5) has been linked to the regulation of T cell survival, and polymorphisms in the human GIMAP5 gene associate with autoimmune disorders. The BioBreeding diabetes-prone (BBDP) rat has a mutation in the Gimap5 gene that leads to spontaneous apoptosis of peripheral T cells by an unknown mechanism. Because Gimap5 localizes to the endoplasmic reticulum (ER), we hypothesized that absence of functional Gimap5 protein initiates T cell death through disruptions in ER homeostasis. We observed increases in ER stress-associated chaperones in T cells but not thymocytes or B cells from Gimap52/ 2 BBDP rats. We then discovered that ER stress-induced apoptotic signaling through C/EBP-homologous protein (CHOP) occurs in Gimap52/ 2 T cells. Knockdown of CHOP by siRNA protected Gimap52/ 2 T cells from ER stress-induced apoptosis, thereby id