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J. Biol. Chem., Vol. 283, Issue 50, 34954-34965, December 12, 2008

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Alix and ALG-2 Are Involved in Tumor Necrosis Factor Receptor 1-induced Cell Death^*

Anne-Laure Mahul-Mellier¹, Flavie Strappazzon², Anne Petiot, Christine Chatellard-Causse, Sakina Torch, Béatrice Blot, Kimberley Freeman, Loriane Kuhn^¶||, Jérome Garin^¶||, Jean-Marc Verna, Sandrine Fraboulet³, and Rémy Sadoul⁴

From the INSERM, U836, Equipe 2, Neurodégénérescence et Plasticité, Grenoble F-38042, France, ^¶Commissariat à l'Énergie Atomique, Departement des Sciences du Vivant Laboratoire d'Etude de la Dynamique des Protéomes, Grenoble F-38054, France, ^||INSERM, U880, Grenoble F-38054, France, and the Université Joseph Fourier, Grenoble Institut des Neurosciences, Grenoble F-38042, France

Alix/AIP1 regulates cell death in a way involving interactions with the calcium-binding protein ALG-2 and with proteins of ESCRT (endosomal sorting complex required for transport). Using mass spectrometry we identified caspase-8 among proteins co-immunoprecipitating with Alix in dying neurons. We next demonstrated that Alix and ALG-2 interact with pro-caspase-8 and that Alix forms a complex with the TNF receptor-1 (TNF-R1), depending on its capacity to bind ESCRT proteins. Thus, Alix and ALG-2 may allow the recruitment of pro-caspase-8 onto endosomes containing TNF-R1, a step thought to be necessary for activation of the apical caspase. In line with this, expression of Alix deleted of its ALG-2-binding site (AlixALG-2) significantly reduced TNF-R1-induced cell death, without affecting endocytosis of the receptor. In a more physiological setting, we found that programmed cell death of motoneurons, which can be inhibited by AlixALG-2, is regulated by TNF-R1. Taken together, these results highlight Alix and ALG-2 as new actors of the TNF-R1 pathway.

Received for publication, April 24, 2008 , and in revised form, October 1, 2008.

^* This work was supported in part by INSERM, the University Joseph Fourier, and grants from the Association Française contre les Myopathies, the Association pour la Recherche sur la Sclérose Latérale Amyotrophique, and the Association pour la Recherche contre le Cancer. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by a fellowship from the Association Française contre les Myopathies. Present address: Imperial College London, Experimental Medicine & Toxicology, London W120NN, UK.

² Present address: European Center for Brain Research, Santa Lucia Foundation, Molecular Neuroembryology Unit, 00143 Rome, Italy.

³ To whom correspondence may be addressed: MRC Functional Genetic Unit, University of Oxford, Dept. of Physiology Anatomy and Genetics, OX1 3QX Oxford, UK. Tel.: 44-1865-282-273; E-mail: sandrine.fraboulet{at}dpag.ox.ac.uk. ⁴ To whom correspondence may be addressed: Grenoble Institute of Neuroscience, Chemin Fortuné Ferrini, BP 170, F-38042 Grenoble, France. Tel.: 33-456-52-05-44; E-mail: remy.sadoul{at}ujf-grenoble.fr.

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