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Originally published as MBC in Press, 10.1091/mbc.E08-01-0068 on March 26, 2008

Vol. 19, Issue 6, 2379-2388, June 2008

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Ear1p and Ssh4p Are New Adaptors of the Ubiquitin Ligase Rsp5p for Cargo Ubiquitylation and Sorting at Multivesicular Bodies

Sébastien Léon, Zoi Erpapazoglou, and Rosine Haguenauer-Tsapis

Institut Jacques Monod, Unité Mixte de Recherche 7592 Centre National de la Recherche Scientifique, Universités Paris 6 et 7, 75251 Paris, France

Submitted January 23, 2008; Revised March 12, 2008; Accepted March 18, 2008
Monitoring Editor: Sandra Lemmon

The ubiquitylation of membrane proteins destined for the vacuole/lysosome is essential for their recognition by the endosomal sorting machinery and their internalization into vesicles of multivesicular bodies (MVBs). In yeast, this process requires Rsp5p, an essential ubiquitin ligase of the Nedd4 family. We describe here two redundant proteins, Ear1p and Ssh4p, required for the vacuolar targeting of several cargoes originating from the Golgi or the plasma membrane. Ear1p is an endosomal protein that interacts with Rsp5p through its PPxY motifs, and it is required for the ubiquitylation of selected cargoes before their MVB sorting. In-frame fusion of cargo to ubiquitin overcomes the need for Ear1p/Ssh4p, confirming a role for these proteins in cargo ubiquitylation. Interestingly, Ear1p is itself ubiquitylated by Rsp5p and targeted to the vacuole. Finally, Ear1p overexpression leads to Rsp5p accumulation at endosomes, interfering with some of its functions in trafficking. Therefore, Ear1p/Ssh4p recruit Rsp5p and assist it in its function at MVBs by directing the ubiquitylation of specific cargoes.

This was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E08-01-0068) on March 26, 2008.

Address correspondence to: Sébastien Léon (leon{at}ijm.jussieu.fr)

Abbreviations used: HECT, Homologous to E6-AP C-Terminus; MVB, multivesicular body; SPRY, splA and ryanodine receptor; VPS, vacuolar protein sorting.






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