Nascent chain folding feeds back on mRNA stability through the ribosome: Consequences for therapeutic mRNA design

In our recently published study in Molecular Cell,1 we describe a surveillance mechanism in which misfolding of the nascent chain slows the elongating ribosome and triggers co-translational decay of the mRNA encoding it (Figure 1). We propose that the ribosome-associated chaperone Zuotin (Zuo1) mediates this feedback, coupling nascent chain folding to ribosome dynamics and mRNA stability. The finding bears directly on how therapeutic mRNAs are designed, because the codon optimization strategies used to accelerate elongation and stabilize transcripts may compromise co-translational folding and engage the very pathway that destabilizes them.