Heat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome.
The cellular-stress response can mediate cellular protection through expression of heat-shock protein (Hsp) 70, which can interfere with the process of apoptotic cell death. Stress-induced apoptosis proceeds through a defined biochemical process that involves cytochrome c, Apaf-1 and caspase proteases. Here we show, using a cell-free system, that Hsp70 prevents cytochrome c/dATP-mediated caspase activation, but allows the formation of Apaf-1 oligomers. Hsp70 binds to Apaf-1 but not to procaspase-9, and prevents recruitment of caspases to the apoptosome complex. Hsp70 therefore suppresses apoptosis by directly associating with Apaf-1 and blocking the assembly of a functional apoptosome.
La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, California 92121, USA.
H M
HM
Beere
B B
BB
Wolf
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K
Cain
D D
DD
Mosser
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A
Mahboubi
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T
Kuwana
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P
Tailor
R I
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Morimoto
G M
GM
Cohen
D R
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Green
D017209:Apoptosis; D053477:Apoptotic Protease-Activating Factor 1; D001665:Binding Sites; D053453:Caspase 9; D020169:Caspases / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D002474:Cell-Free System; D002850:Chromatography, Gel; D003574:Cytochrome c Group / Q000378:metabolism; D003838:Deoxyadenine Nucleotides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004792:Enzyme Precursors / Q000737:chemistry / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006358:Hot Temperature; D006801:Humans; D019169:Jurkat Cells; D008024:Ligands; D046911:Macromolecular Substances; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013379:Substrate Specificity; D014162:Transfection
C506592:APAF1 protein, human; D053477:Apoptotic Protease-Activating Factor 1; D003574:Cytochrome c Group; D003838:Deoxyadenine Nucleotides; D004792:Enzyme Precursors; D018840:HSP70 Heat-Shock Proteins; D008024:Ligands; D046911:Macromolecular Substances; D011506:Proteins; D011994:Recombinant Proteins; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases; C026600:2'-deoxyadenosine triphosphate