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Molecular and Cellular Biology, April 2006, p. 3243-3255, Vol. 26, No. 8
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.8.3243-3255.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Plasma Membrane Localization of Ras Requires Class C Vps Proteins and Functional Mitochondria in Saccharomyces cerevisiae

Geng Wang1 and Robert J. Deschenes1,2*

Department of Biochemistry, University of Iowa, Iowa City, Iowa 52242,1 Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 532262

Received 20 April 2005/ Returned for modification 22 May 2005/ Accepted 17 January 2006

Ras proteins are synthesized as cytosolic precursors, but then undergo posttranslational lipid addition, membrane association, and subcellular targeting to the plasma membrane. Although the enzymes responsible for farnesyl and palmitoyl lipid addition have been described, the mechanism by which these modifications contribute to the subcellular localization of Ras is not known. Following addition of the farnesyl group, Ras associates with the endoplasmic reticulum (ER), where palmitoylation occurs in Saccharomyces cerevisiae. The subsequent translocation of Ras from the ER to the plasma membrane does not require the classical secretory pathway or a functional Golgi apparatus. Vesicular and nonvesicular transport pathways for Ras proteins have been proposed, but the pathway is not known. Here we describe a genetic screen designed to identify mutants defective in Ras trafficking in S. cerevisiae. The screen implicates, for the first time, the class C VPS complex in Ras trafficking. Vps proteins are best characterized for their role in endosome and vacuole membrane fusion. However, the role of the class C Vps complex in Ras trafficking is distinct from its role in endosome and vacuole vesicle fusion, as a mitochondrial involvement was uncovered. Disruption of class C VPS genes results in mitochondrial defects and an accumulation of Ras proteins on mitochondrial membranes. Ras also fractionates with mitochondria in wild-type cells, where it is detected on the outer mitochondrial membrane by virtue of its sensitivity to protease treatment. These results point to a previously uncharacterized role of mitochondria in the subcellular trafficking of Ras proteins.

* Corresponding author. Mailing address: Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226. Phone: (414) 456-8768. Fax: (414) 456-6510. E-mail: rdeschen{at}mcw.edu.

Molecular and Cellular Biology, April 2006, p. 3243-3255, Vol. 26, No. 8
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.8.3243-3255.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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