Bloss Tim A, Witze Eric S, Rothman Joel H
Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, California 93106, USA.
Nature. 2003 Aug 28;424(6952):1066-71. doi: 10.1038/nature01920.
To ensure cell survival, it is essential that the ubiquitous pro-apoptotic machinery is kept quiescent. As death is irreversible, cells must continually integrate developmental information with regulatory inputs to control the switch between repressing and activating apoptosis. Inappropriate activation or suppression of apoptosis can lead to degenerative pathologies or tumorigenesis, respectively. Here we report that Caenorhabditis elegans inhibitor of cell death-1 (ICD-1) is necessary and sufficient to prevent apoptosis. Loss of ICD-1 leads to inappropriate apoptosis in developing and differentiated cells in various tissues. Although this apoptosis requires CED-4, it occurs independently of CED-3--the caspase essential for developmental apoptosis--showing that these core pro-apoptotic proteins have separable roles. Overexpressing ICD-1 inhibits the apoptosis of cells that are normally programmed to die. ICD-1 is the beta-subunit of the nascent polypeptide-associated complex (betaNAC) and contains a putative caspase-cleavage site and caspase recruitment domain. It localizes primarily to mitochondria, underscoring the role of mitochondria in coordinating apoptosis. Human betaNAC is a caspase substrate that is rapidly eliminated in dying cells, suggesting that ICD-1 apoptosis-suppressing activity may be inactivated by caspases.
为确保细胞存活，至关重要的是，普遍存在的促凋亡机制需保持静止状态。由于死亡是不可逆的，细胞必须持续将发育信息与调节输入整合起来，以控制凋亡抑制与激活之间的转换。凋亡的不适当激活或抑制分别会导致退行性病变或肿瘤发生。在此我们报告，秀丽隐杆线虫细胞死亡抑制因子-1（ICD-1）对于预防凋亡是必需且充分的。ICD-1的缺失会导致各种组织中正在发育和分化的细胞发生不适当的凋亡。尽管这种凋亡需要CED-4，但它独立于CED-3（发育性凋亡所必需的半胱天冬酶）而发生，这表明这些核心促凋亡蛋白具有可分离的作用。过表达ICD-1可抑制正常情况下被编程死亡的细胞的凋亡。ICD-1是新生多肽相关复合体（βNAC）的β亚基，包含一个假定的半胱天冬酶切割位点和半胱天冬酶募集结构域。它主要定位于线粒体，这突出了线粒体在协调凋亡中的作用。人βNAC是一种半胱天冬酶底物，在濒死细胞中会迅速被清除，这表明ICD-1的凋亡抑制活性可能会被半胱天冬酶灭活。
