Rabenosyn-5, a novel Rab5 effector, is complexed with hVPS45 and recruitedto endosomes through a FYVE finger domain

Rab5 regulates endocytic membrane traffic by specifically recruiting cytoso lic effector proteins to their site of action on early endosomal membranes. We have characterized a new Rab5 effector complex involved in endosomal fu sion events. This complex includes a novel protein, Rabenosyn-5, which, lik e the previously characterized Rab5 effector early endosome antigen 1 (EEA1 ), contains an FYVE finger domain and is recruited in a phosphatidylinosito l-3-kinase-dependent fashion to early endosomes, Rabenosyn-5 is complexed t o the See1-like protein hVPS45. hVPS45 does not interact directly with Rab5 , therefore Rabenosyn-5 serves as a molecular link between hVPS45 and the R ab5 GTPase, This property suggests that Rabenosyn-5 is a closer mammalian f unctional homologue of yeast Vac1p than EEA1. Furthermore, although both EE A1 and Rabenosyn-5 are required for early endosomal fusion, only overexpres sion of Rabenosyn-5 inhibits cathepsin D processing, suggesting that the tw o proteins play distinct roles in endosomal trafficking. We propose that Ra b5-dependent formation of membrane domains enriched in phosphatidylinositol -3-phosphate has evolved as a mechanism for the recruitment of multiple eff ector proteins to mammalian early endosomes, and that these domains are mul tifunctional, depending on the differing activities of the effector protein s recruited.