西亚试剂:Role of ERO1-α–mediated stimulation of inositol 1,4,5-triph
发布时间:2025-08-18
Role of ERO1-α–mediated stimulation of inositol 1,4,5-triphosphate receptor activity in endoplasmic reticulum stress–induced apoptosis
Gang Li1, Marco Mongillo2,4, King-Tung Chin5, Heather Harding5, David Ron5, Andrew R. Marks2,4, and Ira Tabas1,2,3,4
1 Department of Medicine, 2 Department of Physiology and Cellular Biophysics, 3 Department of Pathology and Cell Biology, and 4 Clyde and Helen Wu Center for Molecular Cardiology, Columbia University, New York, NY 10032 5 Helen L. and Martin S. Kimmel Center for Biology and Medicine, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016
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- (ER oxidase 1 ). In ER-stressed cells, ERO1- is induced by CHOP, and small interfering RNA (siRNA) knockdown of ERO1- suppresses apoptosis. IP3-induced calcium release (IICR) is increased during ER stress, and this response is blocked by siRNA-mediated silencing of ERO1- or IP3R1 and by loss-of-function mutations in Ero1a or Chop. Reconstitution of ERO1- 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-–IP3R pathway.
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