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Vol. 18, Issue 2, 707-720, February 2007

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Characterization of Multiple Multivesicular Body Sorting Determinants within Sna3: A Role for the Ubiquitin Ligase Rsp5

Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905

Submitted August 7, 2006; Revised November 22, 2006; Accepted November 30, 2006
Monitoring Editor: Jean Gruenberg

A subset of proteins that transit the endosomal system are directed into the intralumenal vesicles of multivesicular bodies (MVBs). MVB formation is critical for a variety of cellular functions including receptor down-regulation, viral budding, antigen presentation, and the generation of lysosome-related organelles. Entry of transmembrane proteins into the intralumenal vesicles of a MVB is a highly regulated process that is positively modulated by covalent modification of cargoes with ubiquitin. To identify additional MVB sorting signals, we examined the previously described ubiquitination-independent MVB cargo Sna3. Although Sna3 ubiquitination is not essential, Sna3 MVB sorting is positively modulated by its ubiquitination. Examination of MVB sorting determinants within a form of Sna3 lacking all lysine residues identified two critical regions: an amino-terminal tyrosine-containing region and a carboxyl-terminal PPAY motif. This PPAY motif interacts with the WW domains of the ubiquitin ligase Rsp5, and mutations in either the WW or, surprisingly, the HECT domains of Rsp5 negatively impacted MVB targeting of lysine-minus Sna3. These data indicate that Rsp5 function is required for MVB targeting of Sna3 in a capacity beyond cargo ubiquitination. These results uncover a series of determinants impacting Sna3 MVB sorting, including unexpected roles for Rsp5.

This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E06-08-0680) on December 20, 2006.

The laboratories of both Greg Odorizzi (University of Colorado Boulder; see McNatt et al., 2007) and Rosine Haguenauer-Tsapis (Institut Jacques Monod-CNRS Universites Paris) have also recently uncovered a role for Rsp5 in the sorting of Sna3 into the MVB pathway.

* These authors contributed equally to this work.

Address correspondence to: David J. Katzmann (katzmann.david{at}mayo.edu)

Abbreviations used: CPS, carboxypeptidase S; DPAP B, dipeptidylaminopeptidase B; ESCRT, endosomal sorting complex required for transport; MVB, multivesicular body; ORF, open reading frame; TAP, tandem affinity purification; VPS, vacuolar protein sorting.

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