The IAP-antagonist ARTS initiates caspase activation upstream of cytochrome C and SMAC/Diablo
The IAP-antagonist ARTS initiates caspase activation upstream of cytochrome C and SMAC/Diablo
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DOI：
10.1038/cdd.2011.112
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发表时间：
2012-02-01
影响因子：
12.4
通讯作者：
Larisch, S.
中科院分区：
文献类型：
--
作者：
Edison, N.;Zuri, D.;Larisch, S.
ARTS （Sept4_i2）是一种促凋亡的肿瘤抑制蛋白，可作为X-linked IAP （XIAP）的拮抗剂促进细胞凋亡。一般认为，线粒体外膜通透性（MOMP）发生在半胱天冬酶激活之前，并且是其所必需的。在这里，我们发现ARTS在MOMP上游启动caspase激活。在活细胞中，ARTS定位于线粒体外膜。在响应凋亡信号时，ARTS以不依赖caspase的方式快速转运到细胞质中，在那里它结合XIAP并促进caspase激活。这种易位先于细胞色素C和SMAC/Diablo的释放，而MOMP的正常时间需要ARTS功能。我们还发现，arts诱导的caspase激活会导致促凋亡的Bcl-2家族蛋白Bid的断裂，该蛋白已知会促进MOMP。我们认为ARTS的易位启动了第一波caspase激活，可以促进MOMP。这导致随后释放额外的线粒体因子，包括细胞色素C和SMAC/Diablo，然后放大caspase级联并导致细胞凋亡。细胞死亡与分化（2012）19,356-368；doi: 10.1038 / cdd.2011.112;2011年8月26日在线发布
ARTS (Sept4_i2) is a pro-apoptotic tumor suppressor protein that functions as an antagonist of X-linked IAP (XIAP) to promote apoptosis. It is generally thought that mitochondrial outer membrane permeabilization (MOMP) occurs before activation of caspases and is required for it. Here, we show that ARTS initiates caspase activation upstream of MOMP. In living cells, ARTS is localized to the mitochondrial outer membrane. In response to apoptotic signals, ARTS translocates rapidly to the cytosol in a caspase-independent manner, where it binds XIAP and promotes caspase activation. This translocation precedes the release of cytochrome C and SMAC/Diablo, and ARTS function is required for the normal timing of MOMP. We also show that ARTS-induced caspase activation leads to cleavage of the pro-apoptotic Bcl-2 family protein Bid, known to promote MOMP. We propose that translocation of ARTS initiates a first wave of caspase activation that can promote MOMP. This leads to the subsequent release of additional mitochondrial factors, including cytochrome C and SMAC/Diablo, which then amplifies the caspase cascade and causes apoptosis. Cell Death and Differentiation (2012) 19, 356-368; doi:10.1038/cdd.2011.112; published online 26 August 2011