Timing of ESCRT-0 in EGFR sorting

Sorting of the epidermal growth factor receptor (EGFR) is an excellent model pathway to study receptor dynamics. Upon activation, EGFR is ubiquitinylated and internalised, and subsequently, most of it is sorted into intraluminal vesicles within the vacuolar region of the endosome. Endosomal sorting complexes required for transport (ESCRT)-0 functions early in the ESCRT pathway to sequester ubiquitinylated cargo, but it is not known at which exact point it acts on EGFR, i.e. when it has already entered the vacuolar early endosome, or earlier on. Thus, on page 755, Victoria Allan, Philip Woodman and colleagues analyse the localisation of the ESCRT-0 subunit Hrs (also known as HGS) relative to that of other endosomal markers using an object-based colocalisation software that they developed. They find that a significant portion of Hrs encounters EGFR in peripheral endosomes that lack APPL1, which has been suggested to mark an intermediate compartment en route to vacuolar endosomes; instead, these endosomal structures are positive for the novel early endosomal marker SNX15. Indeed, EGF passes through Hrs-positive peripheral endosomes prior to appearing in vacuolar endosomes, in contrast to what has been suggested previously. Furthermore, the authors find that downstream ESCRTs are recruited later than ESCRT-0, at the time when EGF-containing endosomes mature and acquire the vacuolar marker EEA1. This suggests that the early recruitment of ESCRT-0 to ubiquitinylated cargo might contribute to its efficient transit to the vacuolar endosome.