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First published online July 13, 2004
doi: 10.1242/10.1242/jcs.01212

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N4WBP5A (Ndfip2), a Nedd4-interacting protein, localizes to multivesicular bodies and the Golgi, and has a potential role in protein trafficking

¹ Hanson Institute, IMVS, Frome Road, Adelaide, SA 5000, Australia
² Institute for Molecular Bioscience, University of Queensland, St Lucia, Qld 4072, Australia
³ School of Molecular and Microbial Sciences, University of Queensland, St Lucia, Qld 4072, Australia
⁴ Department of Medicine, Adelaide University, Adelaide, SA 5005, Australia

^* Author for correspondence (e-mail: sharad.kumar{at}imvs.sa.gov.au)

Accepted 10 March 2004

N4WBP5A (Ndfip2) belongs to an evolutionarily conserved group of Nedd4-interacting proteins with two homologues in mammalian species. We have previously shown that N4WBP5A expression in Xenopus oocytes results in increased cell-surface expression of the epithelial sodium channel. N4WBPs are characterized by one or two amino terminal PPxY motifs and three transmembrane domains. Here we show that both PPxY motifs of N4WBP5A mediate interaction with WW domains of Nedd4 and that N4WBP5A can physically interact with the WW domains of several Nedd4-family proteins. N4WBP5A is ubiquitinated and ubiquitination does not significantly affect the turnover of N4WBP5A protein. Ubiquitination of N4WBP5A is enhanced by Nedd4 and Nedd4-2 expression. N4WBP5A localizes to the Golgi, vesicles associated with the Golgi complex and to multivesicular bodies. We show that the ectopic expression of N4WBP5A inhibits receptor-mediated endocytosis of labelled epidermal growth factor. N4WBP5A overexpression inhibits accumulation of EGF in large endocytic/lysosomal vesicles suggestive of a role for N4WBP5A in protein trafficking. We propose that N4WBP5A acts as an adaptor to recruit Nedd4 family ubiquitin-protein ligases to the protein trafficking machinery.

Key words: Nedd4, Ubiquitination, WW domains, Multivesicular bodies

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