The apoptosis inhibitor ARC alleviates the ER stress response to promote β-cell survival

Wendy M. McKimpson, Jeremy Weinberger, Lech Czerski, Min Zheng, Michael T. Crow, Jeffrey E. Pessin, Streamson C. Chua, Jr., Richard N. Kitsis

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Type 2 diabetes involves insulin resistance and β-cell failure leading to inadequate insulin secretion. An important component of β-cell failure is cell loss by apoptosis. Apoptosis repressor with caspase recruitment domain (ARC) is an inhibitor of apoptosis that is expressed in cardiac and skeletal myocytes and neurons. ARC possesses the unusual property of antagonizing both the extrinsic (death receptor) and intrinsic (mitochondria/endoplasmic reticulum [ER]) cell death pathways. Here we report that ARC protein is abundant in cells of the endocrine pancreas, including >99.5% of mouse and 73% of human β-cells. Using genetic gain- and loss-of-function approaches, our data demonstrate that ARC inhibits β-cell apoptosis elicited by multiple inducers of cell death, including ER stressors tunicamycin, thapsigargin, and physiological concentrations of palmitate. Unexpectedly, ARC diminishes the ER stress response, acting distal to protein kinase RNA-like ER kinase (PERK) and inositol-requiring protein 1α, to suppress C/EBP homologous protein (CHOP) induction. Depletion of ARC in isolated islets augments palmitate-induced apoptosis, which is dramatically rescued by deletion of CHOP. These data demonstrate that ARC is a previously unrecognized inhibitor of apoptosis in β-cells and that its protective effects are mediated through suppression of the ER stress response pathway.

Original languageEnglish (US)
Pages (from-to)183-193
Number of pages11
JournalDiabetes
Volume62
Issue number1
DOIs
StatePublished - Jan 2013

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AIDS-Related Complex
Endoplasmic Reticulum Stress
Cell Survival
Apoptosis
Transcription Factor CHOP
Endoplasmic Reticulum
Palmitates
Cell Death
Tunicamycin
Death Domain Receptors
Thapsigargin
Skeletal Muscle Fibers
Inositol
Cellular Structures
Helper-Inducer T-Lymphocytes
Islets of Langerhans
Cardiac Myocytes
Protein Kinases
Type 2 Diabetes Mellitus
Insulin Resistance

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

The apoptosis inhibitor ARC alleviates the ER stress response to promote β-cell survival. / McKimpson, Wendy M.; Weinberger, Jeremy; Czerski, Lech; Zheng, Min; Crow, Michael T.; Pessin, Jeffrey E.; Chua, Jr., Streamson C.; Kitsis, Richard N.

In: Diabetes, Vol. 62, No. 1, 01.2013, p. 183-193.

Research output: Contribution to journalArticle

McKimpson, Wendy M. ; Weinberger, Jeremy ; Czerski, Lech ; Zheng, Min ; Crow, Michael T. ; Pessin, Jeffrey E. ; Chua, Jr., Streamson C. ; Kitsis, Richard N. / The apoptosis inhibitor ARC alleviates the ER stress response to promote β-cell survival. In: Diabetes. 2013 ; Vol. 62, No. 1. pp. 183-193.
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