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PLoS One. 2009;4(5):e5468. doi: 10.1371/journal.pone.0005468. Epub 2009 May 8.

CHOP mediates endoplasmic reticulum stress-induced apoptosis in Gimap5-deficient T cells.

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  • 1Department of 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 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.

PMID:
19424493
[PubMed - indexed for MEDLINE]
PMCID:
PMC2674944
Free PMC Article

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