Mutations gef1, stp22, STP26, and STP27 in Saccharomyces cerevisiae were identified as suppressors of the temperature-sensitive ␣-factor receptor (mutation ste2-3) and arginine permease (mutation can1 ts ). These suppressors inhibited the elimination of misfolded receptors (synthesized at 34°C) as well as damaged surface receptors (shifted from 22 to 34°C). The stp22 mutation (allelic to vps23 [M. Babst and S. Emr, personal communication] and the STP26 mutation also caused missorting of carboxypeptidase Y, and ste2-3 was suppressed by mutations vps1, vps8, vps10, and vps28 but not by mutation vps3. In the stp22 mutant, both the mutant and the wild-type receptors (tagged with green fluorescent protein [GFP]) accumulated within an endosome-like compartment and were excluded from the vacuole. GFP-tagged Stp22p also accumulated in this compartment. Upon reaching the vacuole, cytoplasmic domains of both mutant and wild-type receptors appeared within the vacuolar lumen. Stp22p and Gef1p are similar to tumor susceptibility protein TSG101 and voltage-gated chloride channel, respectively. These results identify potential elements of plasma membrane quality control and indicate that cytoplasmic domains of membrane proteins are translocated into the vacuolar lumen.Plasma membrane proteins link the interior of the cell with the extracellular environment. Removal of defective membrane proteins prevents the accumulation of damage that might otherwise compromise the ability of the cell to maintain electrochemical gradients, transport nutrients, and respond to sensory information. However, degradation of integral membrane proteins presents special problems for the cell because the internal and external sides of the protein are exposed to different biochemical environments. In eucaryotic cells, membrane proteins which have not folded or assembled properly are normally eliminated by the endoplasmic reticulum (ER) quality control process (25); however, examples of post-ER quality control are known (16,31). Degradation of defective membrane proteins in the yeast vacuole has been recognized; however, the molecular details of this process are unknown. This report describes a genetic approach toward elucidating the steps that comprise the quality control of integral plasma membrane proteins.Recent work with Saccharomyces cerevisiae has shown that temperature-sensitive forms of plasma membrane ATPase (Pma1p) (5) and ␣-factor receptors (19) are delivered directly to the vacuole, where they are degraded. In a previous report (19), we described a temperature-sensitive form of the yeast ␣-factor receptor (Ste2-3p) as a model for investigating the consequences of structural defects of integral plasma membrane proteins. Operationally, we define "misfolded receptors" as mutant receptors that are synthesized at the nonpermissive temperature, whereas "damaged cell surface receptors" are receptors that are exposed to the nonpermissive temperature only after they have been expressed at the cell surface. Misfolded receptors are delivered to the va...

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