Author: ["Luigi Ravagnan","Sandeep Gurbuxani","Santos A. Susin","Carine Maisse","Eric Daugas","Naoufal Zamzami","Tak Mak","Marja Jäättelä","Josef M. Penninger","Carmen Garrido","Guido Kroemer"]
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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 complex1,2. 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 flavoprotein3,4. 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. Cite this article
Ravagnan, L., Gurbuxani, S., Susin, S. et al. Heat-shock protein 70 antagonizes apoptosis-inducing factor. Nat Cell Biol 3, 839–843 (2001). https://doi.org/10.1038/ncb0901-839 