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Vol. 19, Issue 2, 475-484, February 2008

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Novel Ist1-Did2 Complex Functions at a Late Step in Multivesicular Body Sorting

Sarah M. Rue^*,,, Sara Mattei^,, Suraj Saksena^||,¶, and Scott D. Emr^*,,||,¶

*Department of Cellular and Molecular Medicine, Division of Biological Sciences, and ^||Howard Hughes Medical Institute, University of California San Diego, La Jolla, CA 92093

Submitted July 25, 2007; Revised November 7, 2007; Accepted November 12, 2007
Monitoring Editor: Sean Munro

In Saccharomyces cerevisiae, integral plasma membrane proteins destined for degradation and certain vacuolar membrane proteins are sorted into the lumen of the vacuole via the multivesicular body (MVB) sorting pathway, which depends on the sequential action of three endosomal sorting complexes required for transport. Here, we report the characterization of a new positive modulator of MVB sorting, Ist1. We show that endosomal recruitment of Ist1 depends on ESCRT-III. Deletion of IST1 alone does not cause cargo-sorting defects. However, synthetic genetic analysis of double mutants of IST1 and positive modulators of MVB sorting showed that ist1 is synthetic with vta1 and vps60, indicating that Ist1 is also a positive component of the MVB-sorting pathway. Moreover, this approach revealed that Ist1-Did2 and Vta1-Vps60 compose two functional units. Ist1-Did2 and Vta1-Vps60 form specific physical complexes, and, like Did2 and Vta1, Ist1 binds to the AAA-ATPase Vps4. We provide evidence that the ist1 mutation exhibits a synthetic interaction with mutations in VPS2 (DID4) that compromise the Vps2-Vps4 interaction. We propose a model in which the Ist1-Did2 and Vta1-Vps60 complexes independently modulate late steps in the MVB-sorting pathway.

These authors contributed equally to this work.

Present addresses: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121;

^¶ Cornell Institute for Cell and Molecular Biology, Cornell University, 307 Biotechnology Building, Ithaca, NY 14853.

Address correspondence to: Scott D. Emr (sde26{at}cornell.edu)

Abbreviations used: CPS, carboxypeptidase S; ESCRT, endosomal sorting complex required for transport; MIM, MIT-interacting motif; MIT, microtubule interacting and trafficking; MVB, multivesicular body; Vps, vacuolar protein sorting.