A Novel Enhancer of the Apaf1 Apoptosome Involved in Cytochrome c-dependent Caspase Activation and Apoptosis

作者：Zhi‐Liang Chu, Frédéric Pio, Zhihua Xie, Kate Welsh, Maryla Krajewska, Stan Krajewski, Adam Godzik, John C. Reed · 发表于：Journal of Biological Chemistry · 年份：2001 · DOI：10.1074/jbc.m006309200 · 被引用次数：183 · 研究领域：Cell death mechanisms and regulation、ATP Synthase and ATPases Research、Heat shock proteins research

Apaf1/CED4 family members play central roles in apoptosis regulation as activators of caspase family cell death proteases. These proteins contain a nucleotide-binding (NB) self-oligomerization domain and a caspase recruitment domain (CARD). A novel human protein was identified, NAC, that contains an NB domain and CARD. The CARD of NAC interacts selectively with the CARD domain of Apaf1, a caspase-activating protein that couples mitochondria-released cytochrome c (cyt-c) to activation of cytosolic caspases. Cyt-c-mediated activation of caspases in cytosolic extracts and in cells is enhanced by overexpressing NAC and inhibited by reducing NAC using antisense/DNAzymes. Furthermore, association of NAC with Apaf1 is cyt c-inducible, resulting in a mega-complex (>1 MDa) containing both NAC and Apaf1 and correlating with enhanced recruitment and proteolytic processing of pro-caspase-9. NAC also collaborates with Apaf1 in inducing caspase activation and apoptosis in intact cells, whereas fragments of NAC representing only the CARD or NB domain suppress Apaf1-dependent apoptosis induction. NAC expression in vivo is associated with terminal differentiation of short lived cells in epithelia and some other tissues. The ability of NAC to enhance Apaf1-apoptosome function reveals a novel paradigm for apoptosis regulation.