ALIX and the multivesicular endosome: ALIX in Wonderland

In yeast and mammalian cells, endosomal sorting complexes required for transport (ESCRT) assist in sorting ubiquitinated proteins into intralumenal vesicles (ILVs) of multivesicular endosomes (MVEs) for degradation in the lysosome/vacuole. In mammalian cells, ESCRTs also drive other topologically identical membrane deformation processes, including cytokinesis, exosome release, and virus budding. Although the ESCRT-associated protein ALIX regulates these mammalian cell-specific functions, it was believed to be dispensable for receptor sorting into ILVs, unlike its yeast homolog Brol. Despite these differences, recent evidence suggests ALIX and Brol share common properties in cargo sorting and ILV formation. We review these commonalities and discuss the role of ALIX in operating 'behind the mirror' during ILV back-fusion with the limiting membrane. We also propose models of how ALIX and some ESCRTs regulate the back-fusion process.