FERARI and cargo adaptors coordinate cargo flow through sorting endosomes

Cellular organization, compartmentalization and cell-to-cell communication are crucially dependent on endosomal pathways. Sorting endosomes provide a transit point for various trafficking pathways and decide the fate of proteins: recycling, secretion or degradation. FERARI (Factors for Endosome Recycling and Rab Interactions) plays a key role in shaping these compartments and coordinates Rab GTPase function with membrane fusion and fission of vesicles through a kiss-and-run mechanism. Here we show that cargo concentration in sorting endosomes determines the length of the kiss between Rab11 and SNX1 structures, presumably by clogging the fusion stalk. Cargo flow from sorting endosomes into Rab11 structures relies on the cargo adaptor SNX6, while cargo retention in the Rab11 endosome is dependent on AP1. Similar to Rab11, Rab5 and Rab10 positive endosomes also interact with the SNX1 tubular network through FERARI-dependent kiss-and-run. We propose that FERARI, together with cargo adaptors, coordinates the vectorial flow of cargo through sorting endosomes.