PHAPI, CAS, and Hsp70 promote apoptosome formation by preventing Apaf-1 aggregation and enhancing nucleotide exchange on Apaf-1
PHAPI, CAS, and Hsp70 promote apoptosome formation by preventing Apaf-1 aggregation and enhancing nucleotide exchange on Apaf-1
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DOI：
10.1016/j.molcel.2008.03.014
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发表时间：
2008-04-25
期刊：
影响因子：
16
通讯作者：
Wang, Xiaodong
中科院分区：
文献类型：
--
作者：
Kim, Hyun-Eui;Jiang, Xuejun;Wang, Xiaodong
在细胞凋亡期间，细胞色素c从线粒体释放到细胞溶质，在那里它结合Apaf-1。Apaf-1 /细胞色素c复合物然后寡聚成七聚体半胱天冬酶-9-活化的寡聚体，其随后活化半胱天冬酶-3和半胱天冬酶-7，或更大的无活性聚集体，这取决于核苷酸dATP/ATP的可用性。一种肿瘤抑制蛋白PHAPI通过一种未知的机制促进溶酶体的形成，从而增强半胱天冬酶的激活。我们在这里报告的鉴定细胞凋亡易感蛋白（CAS）和热休克蛋白70（Hsp 70）作为介质的PHAPI活动。PHAPI、CAS和Hsp 70共同起作用以加速Apaf-1上的核苷酸交换并防止非活性的Apaf-1 /细胞色素c聚集。CAS表达由多种凋亡刺激诱导，包括UV照射。通过RNA干扰（RNAi）在细胞中敲低CAS减弱由UV光诱导的细胞凋亡并导致内源性Apaf-1形成聚集体。这些研究表明PHAPI、CAS和Hsp 70在细胞凋亡过程中起着重要的调节作用。
During apoptosis, cytochrome c is released from mitochondria to the cytosol, where it binds Apaf-1. The Apaf-1 /cytochrome c complex then oligomerizes either into heptameric caspase-9-activating apoptosome, which subsequently activates caspase-3 and caspase-7, or bigger inactive aggregates, depending on the availability of nucleotide dATP/ATP. A tumor suppressor protein, PHAPI, enhances caspase-activation by promoting apoptosome formation through an unknown mechanism. We report here the identification of cellular apoptosis susceptibility protein (CAS) and heat shock protein 70 (Hsp70) as mediators of PHAPI activity. PHAPI, CAS, and Hsp70 function together to accelerate nucleotide exchange on Apaf-1 and prevent inactive Apaf-1 /cytochrome c aggregation. CAS expression is induced by multiple apoptotic stimuli including UV irradiation. Knockdown of CAS by RNA interference (RNAi) in cells attenuates apoptosis induced by UV light and causes endogenous Apaf-1 to form aggregates. These studies indicated that PHAPI, CAS, and Hsp70 play an important regulatory role during apoptosis.