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) play a key role in shaping these compartments and coordinate Rab GTPase function with membrane fusion and fission of vesicles through a kiss-and-run mechanism. Here, we show that FERARI also mediate kiss-and-run of Rab5-positive vesicles with sorting endosomes. During these encounters, cargo flows from Rab5-positive vesicles into sorting endosomes and from there in Rab11-positive vesicles. Cargo flow from sorting endosomes into Rab11 structures relies on the cargo adaptor SNX6, while cargo retention in the Rab11 compartment is dependent on AP1. The available cargo amount appears to regulate the duration of kisses. We propose that FERARI, together with cargo adaptors, coordinate the vectorial flow of cargo through sorting endosomes.