BH3-only BIK regulates BAX, BAK-dependent release of Ca2+ from endoplasmic reticulum stores and mitochondrial apoptosis during stress-induced cell death
BH3-only BIK regulates BAX, BAK-dependent release of Ca2+ from endoplasmic reticulum stores and mitochondrial apoptosis during stress-induced cell death
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DOI：
10.1074/jbc.m500800200
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发表时间：
2005-06-24
影响因子：
4.8
通讯作者：
Shore, GC
中科院分区：
文献类型：
--
作者：
Mathai, JP;Germain, M;Shore, GC
BIK是BCL-2家族的促凋亡BH 3成员，靶向内质网（ER）的膜。它在人类细胞中被诱导，以响应几种应激刺激，包括遗传毒性应激（辐射，阿霉素）和E1 A或p53的过表达，但不是由蛋白质折叠不良引起的ER应激途径。BIK在效应器半胱天冬酶激活上游启动ER中Ca 2+的早期释放。另一方面，在BAX和巴克双重缺陷的幼鼠肾细胞中释放移动的ER Ca 2+储存，对BIK具有抗性，但对异位巴克敏感。p53的过表达刺激巴克向ER的募集，并且其募集和组装成更高级结构都被BIK小干扰RNA抑制。采用小干扰RNA敲除，我们还表明，释放ER Ca 2+和线粒体凋亡在人类上皮细胞需要BIK和Ca 2+调节的目标，动力蛋白相关的GTdR DRP 1，参与p53诱导的线粒体分裂和细胞色素c释放到胞质溶胶。因此，内源性细胞BIK调节BAX、BAK依赖性ER途径，其有助于线粒体凋亡。
BIK, a pro-apoptotic BH3-only member of the BCL-2 family, targets the membrane of the endoplasmic reticulum (ER). It is induced in human cells in response to several stress stimuli, including genotoxic stress ( radiation, doxorubicin) and overexpression of E1A or p53 but not by ER stress pathways resulting from protein malfolding. BIK initiates an early release of Ca2+ from ER upstream of the activation of effector caspases. Release of the mobile ER Ca2+ stores in baby mouse kidney cells doubly deficient in BAX and BAK, on the other hand, is resistant to BIK but is sensitive to ectopic BAK. Over-expression of p53 stimulates recruitment of BAK to the ER, and both its recruitment and assembly into higher order structures is inhibited by BIK small interfering RNA. Employing small interfering RNA knockdowns, we also demonstrated that release of ER Ca2+ and mitochondrial apoptosis in human epithelial cells requires BIK and that a Ca2+-regulated target, the dynamin-related GTPase DRP1, is involved in p53-induced mitochondrial fission and release of cytochrome c to the cytosol. Endogenous cellular BIK, therefore, regulates a BAX, BAK-dependent ER pathway that contributes to mitochondrial apoptosis.