Fig. 8. Model of endosomal protein sorting. (i) Ubiquitylated cargo is retained in a Hrs/clathrin microdomain on the endosome membrane. (ii) The exchange of Hrs and clathrin with a cytosolic pool generates space for the recruitment of ESCRT-I into the coat. (iii) Cargo is efficiently transferred from Hrs to ESCRT-I within the coat, which is maintained through the presence of clathrin. (iv) As the endosome matures, Hrs and clathrin dissociate from the endosome and ESCRT-I remains bound to cargo on the endosome membrane. ESCRT-II and ESCRT-III are recruited, which promotes further sorting of cargo into the forming MVE.