Department of Medicine, Division of Diabetes; Program in Gene Function and Expression; Department of Pathology; Department of Medicine, Division of Endocrinology and Metabolism
Animals; *Apoptosis; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Survival; Diabetes Mellitus, Experimental; Endoplasmic Reticulum; GTP-Binding Proteins; Gene Knockdown Techniques; Heat-Shock Proteins; Lymphocyte Activation; Molecular Chaperones; Rats; Signal Transduction; *Stress, Physiological; T-Lymphocytes; Thymus Gland; Transcription Factor CHOP
Life Sciences | Medicine and Health Sciences
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 Gimap5(-/-) BBDP rats. We then discovered that ER stress-induced apoptotic signaling through C/EBP-homologous protein (CHOP) occurs in Gimap5(-/-) T cells. Knockdown of CHOP by siRNA protected Gimap5(-/-) T cells from ER stress-induced apoptosis, thereby identifying a role for this cellular pathway in the T cell lymphopenia of the BBDP rat. These findings indicate a direct relationship between Gimap5 and the maintenance of ER homeostasis in the survival of T cells.
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Citation: PLoS One. 2009;4(5):e5468. Epub 2009 May 8. Link to article on publisher's site
DOI of Published Version
Pino, Steven C.; O'Sullivan-Murphy, Bryan; Lidstone, Erich A.; Yang, Chaoxing; Lipson, Kathryn L.; Jurczyk, Agata; Diiorio, Philip J.; Brehm, Michael A.; Mordes, John P.; Greiner, Dale L.; Rossini, Aldo A.; and Bortell, Rita, "CHOP mediates endoplasmic reticulum stress-induced apoptosis in Gimap5-deficient T cells" (2009). Open Access Articles. 2081.