Do Alix and ALG-2 really control endosomes for better or for worse?

Alix/AIP1 (ALG-2-interacting protein X/apoptosis-linked-gene-2-interacting protein 1) is an adaptor protein that was first described for its capacity to bind to the calcium-binding protein ALG-2 (apoptosis-linked gene 2), the expression of which seemed necessary for cell death. Over-expression of truncated forms of Alix blocks caspase-dependent and -independent mechanisms of cell death. Numerous observations in yeast and in mammalian cells suggest that Alix controls the making of and trafficking through endosomes called MVBs (multivesicular bodies), which are crucial intermediates within the endolysosomal system. In particular, deletion of Bro1, one of the yeast homologues of Alix, leads to an impairment in the function of MVBs, leading to mis-sorting of proteins normally destined to the vacuole. Mammalian Alix may have a similar function and has been shown to bind to lyso(bis)phosphatidic acid, ESCRT (endosomal sorting complex required for transport) proteins, endophilins and CIN85 (Cbl-interacting protein of 85 kDa), which are all main regulators of the endosomal system. EIAV (equine infectious anaemia virus) and HIV late domains use Alix to recruit the ESCRT machinery in order to bud from the cell surface, underscoring the crucial role of the protein in orchestrating membrane deformation. In this review I develop the hypothesis that the normal function of Alix in the endolysosomal system may be deviated by ALG-2 towards a destructive role during active cell death.