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

TLDR

ER‑stress–induced apoptosis contributes to many diseases, yet the link between ER stress and apoptosis remains incompletely defined. The authors hypothesized that CHOP‑induced ERO1‑α activates the IP3 receptor to mediate ER‑stress–triggered apoptosis. They tested this by manipulating ERO1‑α and IP3R1 expression with siRNA, reconstituting ERO1‑α in Chop‑deficient macrophages, and measuring IP3‑induced calcium release and apoptotic markers. Their data show that CHOP induces ERO1‑α, which enhances IP3‑mediated calcium release; knockdown of ERO1‑α or IP3R1 blocks this release and apoptosis, reconstitution restores it, and both wild‑type and insulin‑resistant ob/ob macrophages exhibit elevated calcium release during ER stress, confirming that the CHOP‑ERO1‑α–IP3R axis drives calcium‑dependent apoptosis.

Abstract

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.