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Published online 23 August 2004. doi:10.1083/jcb.200403139
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 166, Number 5, 717-729
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Article

Bro1 coordinates deubiquitination in the multivesicular body pathway by recruiting Doa4 to endosomes



Natalie Luhtala and Greg Odorizzi

Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309

Address correspondence to Greg Odorizzi, Molecular, Cellular, and Developmental Biology, 347 UCB, University of Colorado, Boulder, CO 80309-0347. Tel.: (303) 735-0179. Fax: (303) 492-7744. email: odorizzi{at}colorado.edu

Ubiquitination directs the sorting of cell surface receptors and other integral membrane proteins into the multivesicular body (MVB) pathway. Cargo proteins are subsequently deubiquitinated before their enclosure within MVB vesicles. In Saccharomyces cerevisiae, Bro1 functions at a late step of MVB sorting and is required for cargo protein deubiquitination. We show that the loss of Bro1 function is suppressed by the overexpression of DOA4, which encodes the ubiquitin thiolesterase required for the removal of ubiquitin from MVB cargoes. Overexpression of DOA4 restores cargo protein deubiquitination and sorting via the MVB pathway and reverses the abnormal endosomal morphology typical of bro1 mutant cells, resulting in the restoration of multivesicular endosomes. We further demonstrate that Doa4 interacts with Bro1 on endosomal membranes and that the recruitment of Doa4 to endosomes requires Bro1. Thus, our results point to a key role for Bro1 in coordinating the timing and location of deubiquitination by Doa4 in the MVB pathway.

Key Words: endosomes; protein sorting; ubiquitin thiolesterase

Abbreviations used in this paper: CPS, carboxypeptidase S; CPY, carboxypeptidase Y; CPY-Inv, CPY-invertase; DIC, differential interference contrast; MVB, multivesicular body; Ub, ubiquitin; UBP, ubiquitin-specific processing protease.


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