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

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

Correspondence to Ira Tabas: iat1{at}columbia.edu

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.

Abbreviations used in this paper: AUC, area under the curve; CHOP, C/EPB homologous protein; IICR, IP3-induced calcium release; IP3, inositol 1,4,5-triphosphate; IP3R, IP3 receptor; MEF, murine embryonic fibroblast; NAC, N-acetyl-Cys; PERK, PKR-like ER kinase; RT-QPCR, reverse transcriptase quantitative PCR; SERCA, sarcoplasmic/ER calcium ATPase; UPR, unfolded protein response; WT, wild type.

© 2009 Li et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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This article has been cited by other articles:

• Short, B. (2009). How ER stress gives cells the CHOP. JCB 186: 768-768 [Full Text]  

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