Nascent chain folding status modulates ribosome dynamics and mRNA stability through the ribosome-associated chaperone Zuo1

Yet, known regulators of ribosome transit, such as codon usage, cannot fully explain transcriptome-wide decay rates. Here, we demonstrate that nascent polypeptide folding status modulates elongation rates, with Zuotin (Zuo1) serving as an essential mediator, and this also influences mRNA stability.

Using reporter constructs encoding co-translationally unstructured proteins and RNA sequencing under proteotoxic stress, we show that Zuo1 is required for the selective destabilization of transcripts whose nascent peptides fail to fold properly. This process is independent of codon optimality but relies on the co-translational mRNA decay factor Not5, which detects slowed ribosomes. 35S labeling indicates that nascent peptide folding defects correlate with reduced elongation rates in a Zuo1-dependent manner, and ribosome profiling reveals that global protein misfolding induces Zuo1-dependent ribosome pausing.