Figure 2.

Examples of trafficking steps that involve UbK63 chains.

Several channels, transporters and receptors undergo modification by UbK63 chains assembled by various E2/E3 pairs. These endocytic cargoes are recognized for sorting to invaginated regions of the plasma membrane by a number of UBD-containing proteins. Some of these receptors are themselves ubiquitylated. Before/after sorting to early endosomes, ubiquitylated endocytic cargoes may be deubiquitylated. Endocytic cargoes join, at the level of MVBs, proteins being trafficked from the trans Golgi network (TGN). Endocytic cargoes and a subset of membrane-bound proteins trafficked from the TGN are ubiquitylated by UbK63 chains. These MVB ubiquitylated cargoes are recognized by UBD-containing proteins of ESCRT complexes -some of which display a better affinity for UbK63 chains than for monoUb- and sorted to invaginating regions of the MVB. They undergo deubiquitylation by endosomal DUBs in the late step of ESCRT-dependent MVB sorting. Many UBD-containing ESCRT proteins themselves undergo ubiquitylation, some possibly with UbK63 chains. UbK63 chain modification of a NPF (nucleation-promoting factor) also leads to branched actin network at the endosome, required for endosome to TGN retrieval.