The newly synthesized soluble proteins granzymes A and B acquire the mannose-6-phosphate signal in the Golgi complex, enabling their association with the mannose-6-phosphate receptor (M6PR) in the trans-Golgi network (TGN) and transport to early endosomes before they are sorted to late endosomes. LAMP1 is sorted by AP complexes (not shown) and transported from the plasma membrane to the endosomes, preferentially to the perimeter membrane of the multivesicular bodies (MVBs) in the sorting endosome and then to the late endosome and cytotoxic granule/LRO. Early endosomes sort cargoes to different destinations. Cargoes can be recycled back to the plasma membrane via fast or slow pathways, delivered to the lysosomes through sorting endosomes and multivesicular bodies, or sorted to the trans-Golgi network. BLOC-1 is involved in the exit of cargoes from an early endosome subdomain toward intermediate/sorting endosomes. γ2-Adaptin has been reported (19) to associate with the ubiquitin machinery, which directs cargo incorporation into intraluminal vesicles (ILVs) of multivesicular bodies by the ESCRT machinery. The study by Rüder et al. in this issue of the JCI (11) reports that EBAG9 associates with and inhibits γ2-adaptin and associates with two BLOC-1 subunits. Loss of EBAG9 enhances the cytotoxic activity of T lymphocytes, likely acting on the endosomal-lysosomal trafficking of the cytotoxic effectors. Although the detailed mechanism accounting for the transport of perforin from the trans-Golgi network to late endosomes is still poorly understood, the findings of Rüder et al. (11) suggest a connection among granzymes and perforin trafficking, the BLOC-1 components, and the ESCRT machinery.