Biogenesis of Multivesicular Body and Protein Sorting: No One of ESCRT,Vps4 and Ubiquitination Can Be Missed

Multivesicular body(MVB) is a dynamic subcellular organelle formed by invagination of the limiting membrane of late endosome.MVB is an essential transport and sorting station for membranes and proteins in eukaryotic organisms.MVB pathway is intimately involved in various processes,including signal transduction,cytokinesis,gene silencing,autophagy,protein quality control and virus budding.The biogenesis of MVB requires more than 20 vacuolar protein sorting(Vps) proteins.Many of them can assemble into four distinct complexes ESCRT 0,Ⅰ,Ⅱ,Ⅲ(endosomal sorting complexs required for transport) on the endosomal membrane.ESCRTs and Vps4 are considered to be the most important components in MVB pathway.ESCRT 0 together with clathrin can form microdomain on endosomal membrane where they cluster ubiquitinated cargo proteins.ESCRTⅠ and Ⅱ can induce the budding of intraluminal vesicles(ILVs),prompt the formation process and sort protein cargoes into ILVs.ESCRTⅢ can constrict,cleave the bud neck and finish the membrane abscission,the last stage of MVB formation.Vps4 can disassemble ESCRT complexes and recycle them.Ubiquitinated cargo proteins and ubiquitination can also regulate the localization and function of ESCRTs.Together,these recent discoveries demonstrate that the sequential and co-ordinated actions of ubiquitinated cargo proteins,ESCRTs and Vps4 are the major driving force for the biogenesis of MVB and protein sorting process.In this review,we focus on the protein-protein interaction and mainly discuss the assembly mechanism,interaction and function of ESCRT complexes and Vps4 high-order oligomers,as well as the regulation of ESCRTs by ubiquitinated proteins and ubiquitination.We also suggest prospective studies based on these discussions.