A model for endocytic trafficking in trypanosomes. A schematic focused on endocytic and recycling pathways is shown, with major Rab GTPases represented as green lozenges, and routes between compartments shown with black arrows. Proposed points of inhibition of specific steps are shown for selected gene products in red. Evidence is summarized from the following previous studies: clathrin-mediated endocytosis at the flagellar pocket (47); Rab5, early endosome (38); EpsinR (50); Rab 11, recycling endosome (39, 53); Vps23/28, multivesicular body (34); Rab28 (58); Vps5, retromer (57); and Rab7, late endosome (54, 59) (also see reference 28). The present study places RME-8 as a mediator of recycling, with ISG65 and ISG75 both accumulating within the endosomal system, and as a consequence of a lack of access to the plasma membrane for internalized molecules, being turned over more rapidly under knockdown conditions. The gray arrows indicate the major routes for ISG trafficking based on the data presented here and in earlier studies (11, 12, 55).