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  • The EMBO Journal (2007) 26, 2527 - 2539
  • doi:10.1038/sj.emboj.7601689

Published online: 19 April 2007

Functional and physical interaction between Bcl-XL and a BH3-like domain in Beclin-1

M Chiara Maiuri1,2,3,4, Gaëtane Le Toumelin5, Alfredo Criollo1,2,3, Jean-Christophe Rain6, Fabien Gautier7, Philippe Juin7, Ezgi Tasdemir1,2,3, Gérard Pierron8, Kostoula Troulinaki9, Nektarios Tavernarakis9, John A Hickman5, Olivier Geneste5,10 and Guido Kroemer1,2,3,10

  1. INSERM U848, Villejuif, France
  2. Institut Gustave Roussy, Villejuif, France
  3. Université Paris Sud—Paris 11, Villejuif, France
  4. Università degli studi di Napoli 'Federico II', Facoltà di Scienze Biotecnologiche, Napoli, Italy
  5. Institut de Recherche Servier, Croissy sur Seine, France
  6. Hybrigenics, Paris, France
  7. INSERM, U601-Equipe 4, University of Nantes, Faculty of MedicineM, Nantes, France
  8. CNRS, FRE 2937, Institut André Lwoff, Villejuif, France
  9. Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology—Hellas, Crete, Greece
  10. These authors contributed equally to this work

Correspondence to:

Guido Kroemer, INSERM U848, Institut Gustave Roussy, PR1, 39 rue Camille Desmoulins, Villejuif 94805, France. Tel.: +33 1 42 11 60 46; Fax: +33 1 42 11 60 47; E-mail: kroemer@igr.fr

Olivier Geneste, Institut de Recherche Servier, 125 chemin de ronde, Croissy sur Seine 78290, France. Tel.: +33 1 55 72 21 68; Fax: +33 1 55 72 21 80; E-mail: olivier.geneste@fr.netgrs.com

Received 13 March 2007; Accepted 15 March 2007

The anti-apoptotic proteins Bcl-2 and Bcl-XL bind and inhibit Beclin-1, an essential mediator of autophagy. Here, we demonstrate that this interaction involves a BH3 domain within Beclin-1 (residues 114–123). The physical interaction between Beclin-1 and Bcl-XL is lost when the BH3 domain of Beclin-1 or the BH3 receptor domain of Bcl-XL is mutated. Mutation of the BH3 domain of Beclin-1 or of the BH3 receptor domain of Bcl-XL abolishes the Bcl-XL-mediated inhibition of autophagy triggered by Beclin-1. The pharmacological BH3 mimetic ABT737 competitively inhibits the interaction between Beclin-1 and Bcl-2/Bcl-XL, antagonizes autophagy inhibition by Bcl-2/Bcl-XL and hence stimulates autophagy. Knockout or knockdown of the BH3-only protein Bad reduces starvation-induced autophagy, whereas Bad overexpression induces autophagy in human cells. Gain-of-function mutation of the sole BH3-only protein from Caenorhabditis elegans, EGL-1, induces autophagy, while deletion of EGL-1 compromises starvation-induced autophagy. These results reveal a novel autophagy-stimulatory function of BH3-only proteins beyond their established role as apoptosis inducers. BH3-only proteins and pharmacological BH3 mimetics induce autophagy by competitively disrupting the interaction between Beclin-1 and Bcl-2 or Bcl-XL.

  • Keywords:

    • apoptosis,
    • autophagy,
    • Bax,
    • Bcl-2,
    • mitochondria