Abstract EN:

Ln an effort to uncover the molecular mechanisms underlying the function of Alix and AIg-2 in cell death, we have found that Alix and AIg-2 can Ca2+-dependently associate with caspase-8 in BHK-21 cells. We investigated the possible existence of an Alix! AIg-2-caspase-8 relationship during cerebellar granule neuron death induced in vitro byeither potassium depletion or Alix overexpression. We showed that Alix is found in a caspase-8-containing complex following K+ depletion-induced CGN apoptosis. Moreover, we demonstrated that caspase-8 functions as initiator caspase in the apoptotic pathway induced by Alix overexpression. Ln a recent work, we gained evidence that the dosure of these Ca2+ channels, which follows the shift to K5 medium,could trigger compensatory Ca2+ mobilization from intracellular stores (Strappazzon, 2007). This prompted us to tum our attention to the putative functional relevance of Alix!Alg-2-caspase-8 interaction to ER stress-induced death. Using both dividing BHK-21 cells and post-mitotic CGN exposed to the ER stressor thapsigargin, we gathered several evidence supporting the idea that Alix, like its binding partner AIg-2, is involved in ER stress-induced death, linking specifficaly two initiator caspases: caspase-8 and -9. Overall our findings suggest that Alix, through its association with AIg-2, is a key mediator of the apoptotic Ca2+ signaling machinery. We also demonstrates the role of Pyk2 in mediating the trophic effect of membrane depolarization in CGN and its possible involvement in survival via the regulation of the binding between Alix and AIg-2 through phosphorylation of Alix.