Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1α
Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1α
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DOI：
10.1126/science.1123480
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发表时间：
2006-04-28
期刊：
影响因子：
56.9
通讯作者：
Korsmeyer, SJ
中科院分区：
文献类型：
--
作者：
Hetz, C;Bernasconi, P;Korsmeyer, SJ
内质网（ER）中错误折叠蛋白的积累引发适应性应激反应，称为未折叠蛋白反应（UPR），由内质网跨膜蛋白激酶和核糖核酸内切肌醇要求酶-1 α (IRE1 α)介导。我们在缺乏促凋亡BCL-2家族成员BAX和BAK[双敲除（DKO）]的小鼠中研究了UPR信号事件。DKO小鼠对tunicamycin诱导的肝脏内质网应激反应异常，出现广泛的组织损伤，IRE1底物x- box结合蛋白1及其靶基因的表达降低。er应激的DKO细胞显示IRE1a信号缺失。BAX和BAK与IRE1 α的胞质结构域形成蛋白质复合物，这对IRE1 α的激活至关重要。因此，BAX和BAK在内质网膜上起作用，激活IRE1 α信号，并在核心凋亡通路成员和UPR之间提供物理联系。
Accumulation of misfolded protein in the endoplasmic reticulum (ER) triggers an adaptive stress response-termed the unfolded protein response (UPR)-mediated by the ER transmembrane protein kinase and endoribonuclease inositol-requiring enzyme-1 alpha (IRE1 alpha). We investigated UPR signaling events in mice in the absence of the proapoptotic BCL-2 family members BAX and BAK [double knockout (DKO)]. DKO mice responded abnormally to tunicamycin-induced ER stress in the liver, with extensive tissue damage and decreased expression of the IRE1 substrate X-box-binding protein 1 and its target genes. ER-stressed DKO cells showed deficient IRE1a signaling. BAX and BAK formed a protein complex with the cytosolic domain of IRE1 alpha that was essential for IRE1 alpha activation. Thus, BAX and BAK function at the ER membrane to activate IRE1 alpha signaling and to provide a physical link between members of the core apoptotic pathway and the UPR.