Endogenous targets of Zuo1-mediated mRNA surveillance encode proteins with higher predicted disorder

Zuo1 slows elongating ribosomes in response to nascent peptide misfolding, which in turn triggers co-translational decay of the transcript. The endogenous substrates of this pathway have remained undefined. Using RNA-sequencing and ribosome profiling of unstressed wild-type and zuo1Δ cells, we identified transcripts that accumulate in the absence of Zuo1, representing mRNAs normally downregulated by Zuo1-mediated surveillance. Proteins encoded by these transcripts displayed higher predicted disorder across multiple metrics, were enriched in basic residues, were depleted of proline residues, and were shorter in length. Ribosome profiling revealed that Zuo1 target transcripts exhibited higher ribosome occupancy in the presence of Zuo1, and the ratio of wild-type to zuo1Δ ribosome occupancy positively correlated with predicted disorder. These findings indicate that Zuo1 surveillance acts preferentially on transcripts encoding nascent chains that fail to acquire stable structure.