CHOP mediates endoplasmic reticulum stress-induced apoptosis in Gimap5-deficient T cells
Authors
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.
Bortell, Rita
UMass Chan Affiliations
Department of Medicine, Division of Endocrinology and MetabolismDepartment of Pathology
Program in Gene Function and Expression
Department of Medicine, Division of Diabetes
Document Type
Journal ArticlePublication Date
2009-05-09Keywords
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
Metadata
Show full item recordAbstract
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.Source
PLoS One. 2009;4(5):e5468. Epub 2009 May 8. Link to article on publisher's siteDOI
10.1371/journal.pone.0005468Permanent Link to this Item
http://hdl.handle.net/20.500.14038/39281PubMed ID
19424493Related Resources
Link to Article in PubMedRights
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.ae974a485f413a2113503eed53cd6c53
10.1371/journal.pone.0005468