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Department of Cell Biology and Anatomy, The Johns Hopkins
University School of Medicine, Baltimore, Maryland 21205
We are studying the intracellular trafficking of the multispanning
membrane protein Ste6p, the a-factor transporter in
Saccharomyces cerevisiae and a member of the ATP-binding
cassette superfamily of proteins. In the present study, we have used
Ste6p as model for studying the process of endoplasmic reticulum (ER) quality control, about which relatively little is known in yeast. We
have identified three mutant forms of Ste6p that are aberrantly ER
retained, as determined by immunofluorescence and subcellular fractionation. By pulse-chase metabolic labeling, we demonstrate that
these mutants define two distinct classes. The single member of Class
I, Ste6-166p, is highly unstable. We show that its degradation involves the ubiquitin-proteasome system, as indicated by its in vivo
stabilization in certain ubiquitin-proteasome mutants or when cells
are treated with the proteasome inhibitor drug MG132. The two Class II
mutant proteins, Ste6-13p and Ste6-90p, are hyperstable relative to
wild-type Ste6p and accumulate in the ER membrane. This represents the
first report of a single protein in yeast for which distinct mutant
forms can be channeled to different outcomes by the ER quality control
system. We propose that these two classes of ER-retained Ste6p mutants
may define distinct checkpoint steps in a linear pathway of ER quality
control in yeast. In addition, a screen for high-copy suppressors of
the mating defect of one of the ER-retained ste6 mutants has
identified a proteasome subunit, Hrd2p/p97, previously implicated in
the regulated degradation of wild-type hydroxymethylglutaryl-CoA
reductase in the ER membrane.
Corresponding author.
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