Genetics, Vol. 167, 107-117, May 2004, Copyright © 2004

Yeast Mn2+ Transporter, Smf1p, Is Regulated by Ubiquitin-Dependent Vacuolar Protein Sorting

Lorena Egueza, Young-Sook Chunga, Ajay Kuchibhatlaa, Madan Paidhungatb, and Stephen Garretta
a Department of Microbiology and Molecular Genetics and Graduate School of Biomedical Sciences, University of Medicine and Dentistry-New Jersey Medical School, Newark, New Jersey 07103-2714
b Maxygen, Redwood City, California 94063

Corresponding author: Stephen Garrett, UMDNJ-New Jersey Medical School, ICPH Bldg., 225 Warren St., P.O. Box 1709, Newark, NJ 07101-1709., garretst{at}umdnj.edu (E-mail)

Communicating editor: B. J. ANDREWS

Conditional cdc1(Ts) mutants of S. cerevisiae arrest with a phenotype similar to that exhibited by Mn2+-depleted cells. Sequence similarity between Cdc1p and a class of Mn2+-dependent phosphoesterases, as well as the observation that conditional cdc1(Ts) growth can be ameliorated by Mn2+ supplement, suggests that Cdc1p activity is sensitive to intracellular Mn2+ levels. This article identifies several previously uncharacterized cdc1(Ts) suppressors as class E vps (vacuolar protein sorting) mutants and shows that these, as well as other vps mutants, accumulate high levels of intracellular Mn2+. Yeast VPS genes play a role in delivery of membrane transporters to the vacuole for degradation, and we show that the vps mutants accumulate elevated levels of the high-affinity Mn2+ transporter Smf1p. cdc1(Ts) conditional growth is also alleviated by mutations, including doa4 and ubc4, that compromise protein ubiquitination, and these ubiquitination defects are associated with Smf1p accumulation. Epistasis studies show that these suppressors require functional Smf1p to alleviate the cdc1(Ts) growth defect, whereas Smf1p is dispensable for cdc1(Ts) suppression by a mutation (cos16/per1) that does not influence intracellular Mn2+ levels. Because Smf1p is ubiquitinated in vivo, we propose that Smf1p is targeted to the vacuole for degradation by ubiquitination-dependent protein sorting.





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