Figure 1. Cul3-based E3-ligase complexes regulate endosome maturation. Cul3 is required during the IAV infection cycle, when the virus penetrates from late endosomes into the cytoplasm. Likewise, Cul3 regulates EGFR trafficking, and its depletion delays lysosomal EGFR degradation. Indeed, without Cul3, the morphology of Rab7-containing vesicles is highly distorted, increased in size and mostly devoid of intra-luminal vesicles in Cul3-depleted cells, while Rab5-containing vesicles appear normal. Because Cul3 functions as a scaffolding molecule to assemble distinct E3-ligase complexes with BTB-domain containing substrate-adaptors, these studies imply that Cul3-mediated ubiquitination of unknown substrates regulates maturation of late endosomes. However, defects in earlier steps of endocytic trafficking may be masked by the dominant endosome maturation defects in Cul3-depleted cells.