Nascent chain misfolding slows translation and stimulates co-translational mRNA decay

Yet, codon usage, a known regulator of ribosome transit, cannot fully explain transcriptome-wide decay rates. Here, we demonstrate that nascent polypeptide folding modulates elongation rates, with Zuotin (Zuo1) serving as an essential mediator.

Using reporter constructs and RNA sequencing, we show that Zuo1 is essential for the selective destabilization of transcripts encoding co-translationally misfolded proteins. This process is independent of codon optimality but relies on co-translational mRNA decay factor Not5, which detects slowed ribosomes. Ribosome profiling reveals that global protein misfolding induces Zuo1-dependent ribosome stalling. 35S labeling confirms that nascent peptide misfolding directly slows elongating ribosomes in a Zuo1-dependent manner.