Role of ERO1-alpha-mediated stimulation of inositol 1,4,5-triphosphate receptor activity in endoplasmic reticulum stress-induced apoptosis.
Role of ERO1-alpha-mediated stimulation of inositol 1,4,5-triphosphate receptor activity in endoplasmic reticulum stress-induced apoptosis.
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DOI：
10.1083/jcb.200904060
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发表时间：
2009-09-21
期刊：
影响因子：
--
通讯作者：
Tabas I
中科院分区：
文献类型：
--
作者：
Li G;Mongillo M;Chin KT;Harding H;Ron D;Marks AR;Tabas I
CHOP打开ERO1-α以通过IP3R释放钙，并响应于ER应激而触发细胞死亡。
内塑性网状（ER）应力诱导的凋亡与许多疾病有关，但是将ER应激与凋亡联系起来的机制是基于C/EPB同源蛋白（CHOP）和ER钙在凋亡中的作用而无法完全理解的。涉及肌醇1,4,5-三磷酸盐（IP3）受体（IP3R）的激活，通过Chop诱导的ERO1-α（ER氧化酶1α）激活。 ERO1-α由CHOP诱导，而ERO1-α的小干扰RNA（siRNA）抑制了IP3诱导的钙释放（IICR），在ER应激期间增加了。 α或IP3R1以及通过ERO1A或CHOP的功能丧失突变。在体内，野生型小鼠的巨噬细胞（而不是CHOP - / - 小鼠）在用ER应激源性肌霉素挑战动物时，IICR升高了。 。
CHOP turns on ERO1-α to release calcium via IP3R and trigger cell death in response to ER stress. 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-α (ER oxidase 1 α). In ER-stressed cells, ERO1-α is induced by CHOP, and small interfering RNA (siRNA) knockdown of ERO1-α suppresses apoptosis. IP3-induced calcium release (IICR) is increased during ER stress, and this response is blocked by siRNA-mediated silencing of ERO1-α or IP3R1 and by loss-of-function mutations in Ero1a or Chop. Reconstitution of ERO1-α 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-α–IP3R pathway.
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