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Heat-shock protein 70 antagonizes apoptosis-inducing factor

Nature Cell Biology volume 3, pages 839–843 (2001)Cite this article

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.

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Figure 1: Hsp70-mediated resistance of Apaf-1−/− MEFs to serum withdrawal.
Figure 2: Hsp70 effects on AIF activities determined in a cell-free system.
Figure 3: Hsp70 antagonizes AIF cytotoxicity.
Figure 4: Domains of Hsp70 required for AIF binding and inactivation.

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Acknowledgements

We thank H. K. Lorenzo for helpful suggestions as well as D. Métivier and J. M. Bruey for technical help. This work has been supported by a special grant from the Ligue Nationale contre le Cancer, grants from ANRS, FRM, and the European Commission (to G.K.), as well as grants from the Comité Val de Marne et la Nièvre de la Ligue contre le Cancer. L.R. and S.G. have PhD fellowships from the French Ministry of Science and Technology, and from INSERM, respectively.

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Author notes

  1. Carmen Garrido and Guido Kroemer: These authors contributed equally to this work

Authors and Affiliations

  1. CNRS UMR 1599, Institute Gustave Roussy, Pavillon de Recherche 1, 39 rue Camille Desmoulins, Villejuif, 94805, France

    Luigi Ravagnan, Santos A. Susin, Carine Maisse, Eric Daugas, Naoufal Zamzami & Guido Kroemer

  2. INSERM U-517, Faculty of Medicine and Pharmacy, 7 Boulevard Jeanne d'Arc, Dijon, 21033, France

    Sandeep Gurbuxani & Carmen Garrido

  3. Assistance Publique – Hôpitaux de Paris, Service de Néphrologie B, Hôpital Tenon, 20 rue de la Chine, Paris, F-75020, France

    Eric Daugas

  4. Department of Medical Biophysics and Immunology, The Amgen Institute and Ontario Cancer Institute, University of Toronto, Toronto, M5G 2C1, Ontario, Canada

    Tak Mak & Josef M. Penninger

  5. Apoptosis Laboratory, Institute of Cancer Biology, Danish Cancer Society, Strandboulevarden 49, Copenhagen, DK-2100, Denmark

    Marja Jäättelä

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Correspondence to Guido Kroemer.

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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

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