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Alix, a protein regulating endosomal trafficking, is involved in neuronal death.

Abstract : Alix/AIP1 is a cytoplasmic protein, which was first characterized as an interactor of ALG-2, a calcium-binding protein necessary for cell death. Alix has also recently been defined as a regulator of the endo-lysosomal system. Here we have used post-mitotic cerebellar neurons to test Alix function in caspase-dependent and -independent cell death. Indeed, these neurons survived when cultured in 25 mm potassium-containing medium but underwent apoptosis soon after the extracellular potassium was lowered to 5 mm. In agreement with other studies, we show that caspases are activated after K+ deprivation, but that inhibition of these proteases, using the pancaspase inhibitor boc-aspartyl(OMe)-fluoromethylketone, has no effect on cell survival. Transfection experiments demonstrated that Alix overexpression is sufficient to induce caspase activation, whereas overexpression of its C-terminal half, Alix-CT, blocks caspase activation and cell death after K+ deprivation. We also define a 12-amino acid PXY repeat of the C-terminal proline-rich domain necessary for binding ALG-2. Deletion of this domain in Alix or in Alix-CT abolished the effects of the overexpressed proteins on neuronal survival, demonstrating that the ALG-2-binding region is crucial for the death-modulating function of Alix. Overall, these findings define the Alix/ALG-2 complex as a regulator of cell death controlling both caspase-dependent and -independent pathways. They also suggest a molecular link between the endo-lysosomal system and the effectors of the cell death machinery.
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Contributor : Sandrine Fraboulet <>
Submitted on : Tuesday, July 12, 2011 - 5:38:17 PM
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Yaël Trioulier, Sakina Torch, Béatrice Blot, Nadine Cristina, Christine Chatellard-Causse, et al.. Alix, a protein regulating endosomal trafficking, is involved in neuronal death.. Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2004, 279 (3), pp.2046-52. ⟨10.1074/jbc.M309243200⟩. ⟨inserm-00381892⟩



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