ESCRTing the RABs through conversion.

The endosomal system is essential for the intra- and intercellular communication in cells and multicellular organisms. It is involved in the secretion of signaling factors and serves as a venue for signaling receptors from the plasma membrane, which are endocytosed after ligand binding. Many internalized receptor-ligand complexes and numerous other endocytosed proteins arrive at the Rab5-positive early endosome, where they will be sorted. Cargoes marked with ubiquitin are bound by endosomal sorting complex required for transport (ESCRT)-0 and ESCRT-I complexes to initiate their degradation. The remaining cargoes are recycled back to the plasma membrane or the trans-Golgi network. To degrade ubiquitinated cargoes, the early endosome has to mature into a late endosomal structure, the multivesicular body (MVB). This procedure requires the Rab5-to-Rab7 conversion, mediated by the RABEX5-MON1/CCZ1 RabGEF cascade. Moreover, cargoes destined for degradation have to be packaged into intraluminal vesicles (ILVs) through ESCRT-III and Vps4. The matured late endosome or MVB finally fuses with a lysosome to degrade the cargo. Although ESCRT-mediated ILV formation and Rab conversion are well-characterized processes during endosome maturation, it remained until recently unclear whether these processes are connected. Lately, several studies were published illuminating the relationship of ESCRT functions and Rab conversion. Here, we review the current knowledge on the role of the ESCRT machinery in cargo degradation and RABEX5 regulation and MON1/CCZ1-mediated Rab conversion during endosome maturation. Moreover, we propose a model on the regulatory role of ESCRT functions during endosome maturation.