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K63-linked ubiquitin chains as a specific signal for protein sorting into the multivesicular body pathway

Laboratoire de Physiologie Moléculaire de la Cellule, Institut de Biologie et de Médecine Moléculaires, Université Libre de Bruxelles, 6041 Gosselies, Belgium

Correspondence to Bruno André: bran{at}ulb.ac.be

A growing number of yeast and mammalian plasma membrane proteins are reported to be modified with K63-linked ubiquitin (Ub) chains. However, the relative importance of this modification versus monoubiquitylation in endocytosis, Golgi to endosome traffic, and sorting into the multivesicular body (MVB) pathway remains unclear. In this study, we show that K63-linked ubiquitylation of the Gap1 permease is essential for its entry into the MVB pathway. Carboxypeptidase S also requires modification with a K63-Ub chain for correct MVB sorting. In contrast, monoubiquitylation of a single target lysine of Gap1 is a sufficient signal for its internalization from the cell surface, and Golgi to endosome transport of the permease requires neither its ubiquitylation nor the Ub-binding GAT (Gga and Tom1) domain of Gga (Golgi localizing, gamma-ear containing, ARF binding) adapter proteins, the latter being crucial for subsequent MVB sorting of the permease. Our data reveal that K63-linked Ub chains act as a specific signal for MVB sorting, providing further insight into the Ub code of membrane protein trafficking.

Abbreviations used in this paper: CPS, carboxypeptidase S; DUB, deubiquitylating enzyme; ESCRT, endosomal sorting complex required for transport; GAT, Gga and Tom1; Gga, Golgi localizing, gamma-ear containing, ARF binding; MVB, multivesicular body; Ub, ubiquitin.

© 2009 Lauwers et al.
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