CHOP mediates endoplasmic reticulum stress-induced apoptosis in Gimap5-deficient T cells.
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.
Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
Steven C
SC
Pino
Bryan
B
O'Sullivan-Murphy
Erich A
EA
Lidstone
Chaoxing
C
Yang
Kathryn L
KL
Lipson
Agata
A
Jurczyk
Philip
P
diIorio
Michael A
MA
Brehm
John P
JP
Mordes
Dale L
DL
Greiner
Aldo A
AA
Rossini
Rita
R
Bortell
D000818:Animals; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D002470:Cell Survival; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000473:pathology*; D019204:GTP-Binding Proteins / Q000172:deficiency*; D055785:Gene Knockdown Techniques; D006360:Heat-Shock Proteins / Q000378:metabolism; D008213:Lymphocyte Activation; D018832:Molecular Chaperones / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D013312:Stress, Physiological; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism*; D013950:Thymus Gland / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP
D019204:GTP-Binding Proteins; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D051742:Transcription Factor CHOP; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; C494977:Gimap5 protein, rat