microRNAs slow translating ribosomes to prevent protein misfolding in eukaryotes

Slower translation rates reduce protein misfolding. Such reductions in speed can be mediated by the presence of non‐optimal codons, which allow time for proper folding to occur. Although this phenomenon is conserved from bacteria to humans, it is not known whether there are additional eukaryote‐specific mechanisms which act in the same way. MicroRNAs (miRNAs), not present in prokaryotes, target both coding sequences (CDS) and 3′ untranslated regions (UTR). Given their low suppressive efficiency, it has been unclear why miRNAs are equally likely to bind to a CDS. Here, we show that miRNAs transiently stall translating ribosomes, preventing protein misfolding with little negative effect on protein abundance. We first analyzed ribosome profiles and miRNA binding sites to examine whether miRNAs stall ribosomes. Furthermore, either global or specific miRNA deficiency accelerated ribosomes and induced aggregation of a misfolding‐prone polypeptide reporter. These defects were rescued by slowing ribosomes using non‐cleaving shRNAs as miRNA mimics. We finally show that proinsulin misfolding, associated with type II diabetes, was resolved by non‐cleaving shRNAs. Our findings provide a eukaryote‐specific mechanism of co‐translational protein folding and a previously unknown mechanism of action to target protein misfolding diseases.