1. PHAPI, CAS, and Hsp70 promote apoptosome formation by preventing Apaf-1 aggregation and enhancing nucleotide exchange on Apaf-1.
- Author
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Kim HE, Jiang X, Du F, and Wang X
- Subjects
- Apoptotic Protease-Activating Factor 1 antagonists & inhibitors, Caspase 9 metabolism, Caspase Inhibitors, Cellular Apoptosis Susceptibility Protein antagonists & inhibitors, Cellular Apoptosis Susceptibility Protein genetics, Enzyme Activation, HeLa Cells, Humans, Intracellular Signaling Peptides and Proteins genetics, Nuclear Proteins, Nucleotides metabolism, RNA Interference, RNA-Binding Proteins, Apoptosis, Apoptosomes metabolism, Apoptotic Protease-Activating Factor 1 metabolism, Cellular Apoptosis Susceptibility Protein metabolism, HSP70 Heat-Shock Proteins metabolism, Intracellular Signaling Peptides and Proteins metabolism
- Abstract
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-9 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.
- Published
- 2008
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