Role of ERO1-[alpha]-mediated stimulation of inositol 1,4,5-triphosphate receptor activity, in endoplasmic reticulum stress--induced apoptosis

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 EROI-[alpha] or IP3R1 and by loss-of-function mutations in Erola or Chop. Reconstitution of ER01-[alpha] in [Chop.sup.-/-] macrophages restores ER stress--induced IICR and apoptosis. In vivo, macrophages from wild-type mice but not [Chop.sup.-/-] 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 ER01-[alpha]-IP3R pathway.