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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Copyright: © 2009 Pino et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
DOI of Published Version
PLoS One. 2009;4(5):e5468. Epub 2009 May 8. Link to article on publisher's site
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.