Journal
JOURNAL OF CELL BIOLOGY
Volume 186, Issue 6, Pages 783-792Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200904060
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Funding
- National Institutes of Health (NIH) [HL087123, HL075662, DK47119, ES08681]
- US Army Medical Research and Materiel Command [W81XWH-06-1-0212]
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Endoplasmic reticulum (ER) stress-induced apoptosis is involved in many diseases, but the mechanisms linking ER stress to apoptosis are incompletely understood. Based on roles for C/EPB homologous protein (CHOP) and ER calcium release in apoptosis, we hypothesized that apoptosis involves the activation of inositol 1,4,5-triphosphate (IP3) receptor (IP3R) via CHOP-induced ERO1-alpha (ER oxidase 1 alpha). In ER-stressed cells, ERO1-alpha is induced by CHOP, and small interfering RNA (siRNA) knockdown of ERO1-alpha suppresses apoptosis. IP3-induced calcium release (IICR) is increased during ER stress, and this response is blocked by siRNA-mediated silencing of ERO1-alpha or IP3R1 and by loss-of-function mutations in Ero1a or Chop. Reconstitution of ERO1-alpha in Chop(-/-) macrophages restores ER stress-induced IICR and apoptosis. In vivo, macrophages from wild-type mice but not Chop(-/-) mice have elevated IICR when the animals are challenged with the ER stressor tunicamycin. Macrophages from insulin-resistant ob/ob mice, another model of ER stress, also have elevated IICR. These data shed new light on how the CHOP pathway of apoptosis triggers calcium-dependent apoptosis through an ERO1-alpha-IP3R pathway.
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