Rabenosyn-5, a Novel Rab5 Effector, Is Complexed with Hvps45 and Recruited to Endosomes through a Fyve Finger Domain

doi:10.1083/jcb.151.3.601

Published online 30 October 2000. doi:10.1083/jcb.151.3.601

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© The Rockefeller University Press, 0021-9525/2000//601 $5.00
The Journal of Cell Biology, Volume 151, Number 3, , 2000 601-612

Original Article

Rabenosyn-5, a Novel Rab5 Effector, Is Complexed with Hvps45 and Recruited to Endosomes through a Fyve Finger Domain

Erik Nielsen^a, Savvas Christoforidis^a, Sandrine Uttenweiler-Joseph^b, Marta Miaczynska^a, Frederique Dewitte^c, Matthias Wilm^b, Bernard Hoflack^c, and Marino Zerial^a

^a Max-Planck-Institute for Molecular Cell Biology and Genetics, 01307 Dresden, Germany
^b European Molecular Biology Laboratory, 69117 Heidelberg, Germany
^c Institut de Biologie de Lille, Centre National de la Recherche Scientifique EP 525/Institut Pasteur de Lille 1, 59021 Lille, France
Max-Planck-Institute for Molecular Cell Biology and Genetics, Pfotenhauerstrasse, 01307 Dresden, Germany.49-6221-387-51249-6221-387-232

Rab5 regulates endocytic membrane traffic by specifically recruitingcytosolic effector proteins to their site of action on earlyendosomal membranes. We have characterized a new Rab5 effectorcomplex involved in endosomal fusion events. This complex includesa novel protein, Rabenosyn-5, which, like the previously characterizedRab5 effector early endosome antigen 1 (EEA1), contains an FYVEfinger domain and is recruited in a phosphatidylinositol-3-kinase–dependentfashion to early endosomes. Rabenosyn-5 is complexed to theSec1-like protein hVPS45. hVPS45 does not interact directlywith Rab5, therefore Rabenosyn-5 serves as a molecular linkbetween hVPS45 and the Rab5 GTPase. This property suggests thatRabenosyn-5 is a closer mammalian functional homologue of yeastVac1p than EEA1. Furthermore, although both EEA1 and Rabenosyn-5are required for early endosomal fusion, only overexpressionof Rabenosyn-5 inhibits cathepsin D processing, suggesting thatthe two proteins play distinct roles in endosomal trafficking.We propose that Rab5-dependent formation of membrane domainsenriched in phosphatidylinositol-3-phosphate has evolved asa mechanism for the recruitment of multiple effector proteinsto mammalian early endosomes, and that these domains are multifunctional,depending on the differing activities of the effector proteinsrecruited.

Key Words: endocytosis • Rab5 • hVPS45 • EEA1 • Rabenosyn-5

S. Christoforidis' present address is Laboratory of BiologicalChemistry, Medical School, University of Ioannina, 45110 Ioannina,Greece.

Abbreviations used in this paper: CCV, clathrin-coated vesicle;EEA1, early endosome antigen 1; EGFP, enhanced GFP; EH, E15homology; EST, expressed sequence tag; GFP, green fluorescentprotein; GST, glutathione S-transferase; NSF, N-ethylmaleimide–sensitivefactor; P, phosphate; PC, phosphatidylcholine; PI, phosphatidylinositol;PVC, prevacuolar compartment; SNAP, soluble NSF attachment protein;SNARE, SNAP receptor.

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