Noncoding translation mitigation

Translation is pervasive outside of canonical coding regions, occurring in long noncoding RNAs, canonical untranslated regions and introns(1-4), especially in ageing(4-6), neurodegeneration(5,7) and cancer(8-10). Notably, the majority of tumour-specific antigens are results of noncoding translation(11-13). Although the resulting polypeptides are often nonfunctional, translation of noncoding regions is nonetheless necessary for the birth of new coding sequences(14,15). The mechanisms underlying the surveillance of translation in diverse noncoding regions and how escaped polypeptides evolve new functions remain unclear(10,16-19). Functional polypeptides derived from annotated noncoding sequences often localize to membranes(20,21). Here we integrate massively parallel analyses of more than 10,000 human genomic sequences and millions of random sequences with genome-wide CRISPR screens, accompanied by in-depth genetic and biochemical characterizations. Our results show that the intrinsic nucleotide bias in the noncoding genome and in the genetic code frequently results in polypeptides with a hydrophobic C-terminal tail, which is captured by the ribosome-associated BAG6 membrane protein triage complex for either proteasomal degradation or membrane targeting. By contrast, canonical proteins have evolved to deplete C-terminal hydrophobic residues. Our results reveal a fail-safe mechanism for the surveillance of unwanted translation from diverse noncoding regions and suggest a possible biochemical route for the preferential membrane localization of newly evolved proteins.

Automated summary

Translation is widespread in noncoding regions, especially in ageing, neurodegeneration and cancer. Although most tumor-specific antigens are products of noncoding translation, the resulting polypeptides are often nonfunctional, but necessary for the birth of new coding sequences. The mechanisms underlying the surveillance of translation in noncoding regions and the evolution of escaped polypeptides with new functions are unclear. Functional polypeptides derived from annotated noncoding sequences often localize to membranes. Our study reveals a fail-safe mechanism for monitoring unwanted translation and suggests a biochemical route for the membrane localization of newly evolved proteins.