Skip to main content
Article thumbnail
Location of Repository

CHOP Mediates Endoplasmic Reticulum Stress-Induced Apoptosis in Gimap5-Deficient T Cells

By Steven C. Pino, Bryan O'Sullivan-Murphy, Erich A. Lidstone, Chaoxing Yang, Kathryn L. Lipson, Agata Jurczyk, Philip diIorio, Michael A. Brehm, John P. Mordes, Dale L. Greiner, Aldo A. Rossini and Rita Bortell


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

Topics: Research Article
Publisher: Public Library of Science
OAI identifier:
Provided by: PubMed Central

Suggested articles


  1. (1995). Abnormal lymphocyte subsets in Kuwaiti patients with type-1 insulin-dependent diabetes mellitus and their first-degree relatives.
  2. (2002). Activation of an unfolded protein response during differentiation of antibody-secreting B cells.
  3. (2006). Activation of the integrated stress response during T helper cell differentiation.
  4. (2009). Analysis of the rat Iddm14 diabetes susceptibility locus in multiple rat strains: identification of a susceptibility haplotype in the Tcrb-V locus. Mamm Genome, In press.
  5. (1998). Antigen activation rescues recent thymic emigrants from programmed cell death in the BB rat.
  6. (2004). Autoimmune diabetes and the circle of tolerance.
  7. (2008). Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities.
  8. (2006). Cellular response to endoplasmic reticulum stress: a matter of life or death.
  9. (2006). Central tolerance: good but imperfect.
  10. (2004). Comparative analysis of the human gimap gene cluster encoding a novel GTPase family.
  11. (2002). Coupling endoplasmic reticulum stress to the cell death program: role of the ER chaperone GRP78.
  12. (1995). Development and selection of T cells: facts and puzzles.
  13. (1996). Developmental regulation of V(D)J recombination and lymphocyte differentiation.
  14. (1999). Elevated apoptosis of peripheral T lymphocytes in diabetic BB rats.
  15. (2006). Endoplasmic reticulum architecture: structures in flux.
  16. (2006). Endoplasmic reticulum stress and apoptosis.
  17. (2005). Endoplasmic reticulum stress signaling transmitted by ATF6 mediates apoptosis during muscle development.
  18. (2002). Endoplasmic reticulum stress-mediated apoptosis in pancreatic beta-cells.
  19. (2007). ER stress triggers apoptosis by activating BH3-only protein Bim.
  20. (2007). GIMAP5 regulates mitochondrial integrity from a distinct subcellular compartment.
  21. (1998). High frequency apoptosis of recent thymic emigrants in the liver of lymphopenic diabetes-prone BioBreeding rats.
  22. (2007). IA-2 autoantibodies in incident type I diabetes patients are associated with a polyadenylation signal polymorphism in GIMAP5.
  23. (2006). IAN family critically regulates survival and development of T lymphocytes.
  24. (2003). Ian4 is required for mitochondrial integrity and T cell survival.
  25. (2003). Impact of endoplasmic reticulum stress pathway on pancreatic beta-cells and diabetes mellitus.
  26. (2008). Impaired survival of peripheral T cells, disrupted NK/NKT cell development, and liver failure in mice lacking gimap5.
  27. (2003). Irod/Ian5: an inhibitor of gamma-radiation- and okadaic acid-induced apoptosis.
  28. (2002). Lymphopenia in the BB rat model of type 1 diabetes is due to a mutation in a novel immune-associated nucleotide (Ian)-related gene.
  29. (2001). Molecular cloning of Ian4: a BCR/ABL-induced gene that encodes an outer membrane mitochondrial protein with GTP-binding activity.
  30. (2002). Orchestrating the unfolded protein response in health and disease.
  31. (2004). Partial activation precedes apoptotic death in T cells harboring an IAN gene mutation.
  32. (2008). Protein kinase C signaling during T cell activation induces the endoplasmic reticulum stress response.
  33. (2006). pXBP1(U) encoded in XBP1 premRNA negatively regulates unfolded protein response activator pXBP1(S) in mammalian ER stress response.
  34. (2004). Rat models of type 1 diabetes: genetics, environment, and autoimmunity.
  35. (2006). Role of the unfolded protein response in cell death.
  36. (2004). Signaling the unfolded protein response from the endoplasmic reticulum.
  37. (1996). Signals from the stressed endoplasmic reticulum induce C/EBP-homologous protein (CHOP/GADD153).
  38. (2002). The diabetes-prone BB rat carries a frameshift mutation in Ian4, a positional candidate of Iddm1.
  39. (2005). The ER chaperone and signaling regulator GRP78/BiP as a monitor of endoplasmic reticulum stress.
  40. (2007). The human GIMAP5 gene has a common polyadenylation polymorphism increasing risk to systemic lupus erythematosus.
  41. (2002). The iddm4 locus segregates with diabetes susceptibility in congenic WF.iddm4 rats.
  42. (2007). The lymphocyte guard-IANs: regulation of lymphocyte survival by IAN/GIMAP family proteins.
  43. (2005). The rat diabetes susceptibility locus Iddm4 and at least one additional gene are required for autoimmune diabetes induced by viral infection.
  44. (1996). The rat T-cell surface protein RT6 is associated with src family tyrosine kinases and generates an activation signal.
  45. (2002). Transcriptional and translational control in the Mammalian unfolded protein response.
  46. (2004). Transgenic rescue demonstrates involvement of the Ian5 gene in T cell development in the rat.
  47. (2002). Translational control in the endoplasmic reticulum stress response.
  48. (2000). Upregulation of BiP and CHOP by the unfolded-protein response is independent of presenilin expression.
  49. (2007). West Nile virus infection activates the unfolded protein response, leading to CHOP induction and apoptosis.

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.