microRNAs slow translating ribosomes to prevent protein misfolding

An evolutionarily conserved mechanism, use of non-optimal codons, slows ribosomes during translation to allow proper folding of nascent polypeptides. However, until now, it was unknown whether any eukaryote-specific mechanisms exist for this purpose. Here, we propose that miRNAs slow translating ribosomes to prevent protein misfolding, with little negative effect on protein abundance. To prove this, we bioinformatically analyze ribosome profiling and miRNA binding sites and biochemically confirm that miRNA deficiency causes severe misfolding, which is rescued by slowing translating ribosomes. We demonstrate that non-cleaving shRNAs, targeting regions where elongation rates become faster in miRNA-deficient cells, improve protein folding with minimal effects on protein abundance. These results reveal broader functionality of miRNAs and a previously unknown mechanism to prevent protein misfolding. One Sentence Summary Eukaryote use of miRNAs prevents protein misfolding in a target-specific manner.