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Genetic Requirements for the Degradation of Translocon‐Associated Proteins

The endoplasmic reticulum (ER) translocon is a molecular channel responsible for moving secreted and endomembrane system proteins across the ER membrane. Proteins that stall within or otherwise aberrantly engage the translocon channel may impair transport of other proteins across the membrane. Proteins that persistently or aberrantly engage the translocon are targeted for degradation via the conserved ER‐resident ubiquitin ligase Hrd1. A better understanding of this system may prove useful in treating elevated cholesterol in humans as, under certain circumstances, the major protein component of low‐density lipoproteins (LDL; bad cholesterol) stalls within the translocon prior to LDL synthesis. Protein co‐factors that assist Hrd1 in targeting other substrates for degradation are dispensable for Hrd1‐dependent degradation of translocon‐obstructing proteins. We hypothesize that Hrd1 requires the function of a distinct cohort of protein co‐factors to recognize and ubiquitylate proteins that aberrantly engage the translocon. We have developed a growth‐based screen to identify genes in Saccharomyces cerevisiae that mediate the degradation of proteins that aberrantly engage the translocon. We fused the His3 enzyme, which is required for histidine biosynthesis, to a model protein that aberrantly engages with the translocon. In this way, histidine prototrophy is an indicator of impaired protein degradation. We introduced this fusion protein into the non‐essential yeast gene knockout collection using Synthetic Genetic Array (SGA) technology. Genes found to be required for degradation of the model translocon‐associated protein may represent therapeutic targets for patients with cholesterol‐related pathology.