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首页> 外文期刊>Molecular and Cellular Biology >Caspase-2 Cleavage of BID Is a Critical Apoptotic Signal Downstream of Endoplasmic Reticulum Stress
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Caspase-2 Cleavage of BID Is a Critical Apoptotic Signal Downstream of Endoplasmic Reticulum Stress

机译：BID的Caspase-2裂解是内质网应激下游的重要凋亡信号。

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The accumulation of misfolded proteins stresses the endoplasmic reticulum (ER) and triggers cell death through activation of the multidomain proapoptotic BCL-2 proteins BAX and BAK at the outer mitochondrial membrane. The signaling events that connect ER stress with the mitochondrial apoptotic machinery remain unclear, despite evidence that deregulation of this pathway contributes to cell loss in many human degenerative diseases. In order to “trap” and identify the apoptotic signals upstream of mitochondrial permeabilization, we challenged Bax?/? Bak?/? mouse embryonic fibroblasts with pharmacological inducers of ER stress. We found that ER stress induces proteolytic activation of the BH3-only protein BID as a critical apoptotic switch. Moreover, we identified caspase-2 as the premitochondrial protease that cleaves BID in response to ER stress and showed that resistance to ER stress-induced apoptosis can be conferred by inhibiting caspase-2 activity. Our work defines a novel signaling pathway that couples the ER and mitochondria and establishes a principal apoptotic effector downstream of ER stress.
机译：折叠错误的蛋白质的积累会向内质网（ER）施加压力，并通过激活线粒体外膜上的多域促凋亡BCL-2蛋白BAX和BAK触发细胞死亡。尽管有证据表明这种通路的失调会导致许多人类退行性疾病中的细胞丢失，但仍不清楚将内质网应激与线粒体凋亡机制联系起来的信号事件。为了“捕获”并识别线粒体通透性上游的凋亡信号，我们挑战了 Bax ？ / ？ Bak ？ / ？小鼠胚成纤维细胞具有ER应激的药理诱导剂。我们发现内质网应激诱导BH3仅蛋白BID的蛋白水解激活作为关键的凋亡开关。此外，我们将caspase-2识别为线粒体蛋白酶，该酶可切割BID以响应ER应激，并表明可通过抑制caspase-2活性赋予对ER应激诱导的细胞凋亡的抗性。我们的工作定义了一条新颖的信号传导途径，该信号传导途径将内质网和线粒体耦合，并在内质网应激下游建立了主要的凋亡效应子。

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