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- Title
Heat-shock protein 70 antagonizes apoptosis-inducing factor.
- Authors
Ravagnan, Luigi; Gurbuxani, Sandeep; Susin, Santos A.; Maisse, Carine; Daugas, Eric; Zamzami, Naoufal; Mak, Tak; Jäättelä, Marja; Penninger, Josef M.; Garrido, Carmen; Kroemer, Guido
- Abstract
Heat-shock protein 70 (Hsp70) has been reported to block apoptosis by binding apoptosis protease activating factor-1 (Apaf-1), thereby preventing constitution of the apoptosome, the Apaf-1/cytochrome c/caspase-9 activation complex. Here we show that overexpression of Hsp70 protects Apaf-1-/- cells against death induced by serum withdrawal, indicating that Apaf-1 is not the only target of the anti-apoptotic action of Hsp70. We investigated the effect of Hsp70 on apoptosis mediated by the caspase-independent death effector apoptosis inducing factor (AIF), which is a mitochondrial intermembrane flavoprotein. In a cell-free system, Hsp70 prevented the AIF-induced chromatin condensation of purified nuclei. Hsp70 specifically interacted with AIF, as shown by ligand blots and co-immunoprecipitation. Cells overexpressing Hsp70 were protected against the apoptogenic effects of AIF targeted to the extramitochondrial compartment. In contrast, an anti-sense Hsp70 complementary DNA, which reduced the expression of endogenous Hsp70, increased sensitivity to the lethal effect of AIF. The ATP-binding domain of Hsp70 seemed to be dispensable for inhibiting cell death induced by serum withdrawal, AIF binding and AIF inhibition, although it was required for Apaf-1 binding. Together, our data indicate that Hsp70 can inhibit apoptosis by interfering with target proteins other than Apaf-1, one of which is AIF.
- Subjects
HEAT shock proteins; APOPTOSIS; FLAVOPROTEINS
- Publication
Nature Cell Biology, 2001, Vol 3, Issue 9, p839
- ISSN
1465-7392
- Publication type
Article
- DOI
10.1038/ncb0901-839