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Heat shock protein 70 binding inhibits the nuclear import of apoptosis-inducing factor

Oncogene volume 22, pages 6669–6678 (2003)Cite this article

Abstract

Heat shock protein 70 (HSP70) can inhibit apoptosis by neutralizing and interacting with apoptosis-inducing factor (AIF), a mitochondrial flavoprotein that translocates upon apoptosis induction to the nucleus, via the cytosol. Here, we show that only members of the HSP70 family interact with AIF. Systematic deletion mapping revealed the existence of three distinct functional regions in the AIF protein: (1) a region between amino acids 150 and 228 that binds HSP70, (2) a domain between residues 367 and 459 that includes a nuclear localization sequence (NLS) and (3) a C-terminal domain beyond residue 567 required for its chromatin-condensing activity. Deletion of the 150–268 domain completely abolished HSP70 binding and facilitated the nuclear import of AIF, resulting in a gain-of-function phenotype with enhanced AIF-mediated chromatin condensation as compared to wild-type AIF. This gain-of-function phenotype was observed in wild-type control cells (which express low but significant levels of HSP70), yet was lost when AIFΔ150–268 was introduced into HSP70 knockout cells, underscoring the functional importance of the AIF–HSP70 interaction. Altogether, our data demonstrate that AIF inhibition by HSP70 involves cytosolic retention of AIF. Moreover, it appears that endogenous HSP70 protein levels are sufficiently elevated to modulate the lethal action of AIF.

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Acknowledgements

We thank Clayton R Hunt (Department of Radiation Oncology, Washington University School Of Medicine, St Louis, MO 63108, USA), David J Dix (National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, NC 27711, USA) and Marja Jäättelä (Danish Cancer Society, DK-2100, Copenhagen, Denmark) for the MEF HSP70.1, HSP70.3-deficient cells. This work was supported by the Institut National pour la Santé et la Recherche Medicale (INSERM), the Comité Départemental de la Nièvre de la Ligue National contre le Cancer, the Association pour la Recherche contre le Cancer (ARC # 9567 and 5204), the Conseil Régional de Bourgogne (to CG), Ligue Nationale contre le Cancer and the European Commission (QLG1-CT-1999-00739) (to GK). SG was supported by a Poste vert from the INSERM, AP by a fellowship from the Ministère de l'Education Nationale and CC by a fellowship from ARC.

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Author notes

  1. Sandeep Gurbuxani and Elise Schmitt: SG and ES contributed equally to this paper

  2. Guido Kroemer and Carmen Garrido: CG and GK share senior co-authorship

Authors and Affiliations

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

    Sandeep Gurbuxani, Elise Schmitt, Arnaud Parcellier, Arlette Hammann & Carmen Garrido

  2. CNRS UMR 1599, Institute Gustave Roussy, Villejuif, 94805, France

    Celine Cande, Eric Daugas, Ilektra Kouranti & Guido Kroemer

  3. Amgen Inc., Mammalian Genomics, Amgen Center, Thousand Oaks, 91320, CA, USA

    Chris Spahr

  4. Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, UK

    Alena Pance

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  1. Sandeep Gurbuxani
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Correspondence to Carmen Garrido.

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Gurbuxani, S., Schmitt, E., Cande, C. et al. Heat shock protein 70 binding inhibits the nuclear import of apoptosis-inducing factor. Oncogene 22, 6669–6678 (2003). https://doi.org/10.1038/sj.onc.1206794

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