Transport from the plasma membrane to lysosomes occurs through endosomal compartments. The transition between early to late endosomes is thought to be mediated by RAB conversion in which the loss of RAB5 from the endosome and the acquisition of RAB7 to the same membranes takes place and thereby serve as markers for early-to-late endosome maturation. Here we demonstrate that this RAB conversion is the mechanism by which proteins pass from early to late endosomes in C. elegans coelomocytes.

Moreover, we identified SAND-1/Mon1b as the critical switch for RAB conversion in metazoa. SAND-1 serves a dual role in this process. First, it interrupts the positive feedback loop of RAB-5 activation by displacing RABX-5 from endosomal membranes and second it times the recruitment of RAB7 to these same membranes. SAND-1 is recruited to endosomes by coincidence detection of RABX-5 and high PI(3)P levels, where it initiates the activation of RAB-7 by interacting with core components of a RAB7-GEF, the HOPS complex. SAND-1/Mon1b acts as switch and regulates the activity of RAB-5 and RAB-7 by controlling their activation through GEFs.