A unified model for the surveillance of translation in diverse noncoding sequences

Abstract

Translation is pervasive outside of canonical coding regions, occurring in lncRNAs, UTRs, and introns. While the resulting polypeptides are often non-functional, translation in noncoding regions is nonetheless necessary for the birth of new coding regions. The mechanisms underlying the surveillance of translation in diverse noncoding regions and how escaped polypeptides evolve new functions remain unclear. Intriguingly, noncoding sequence-derived functional peptides often localize to membranes. Here, we 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. In contrast, canonical proteins have evolved to deplete C-terminal hydrophobic residues. Our results uncovered 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.HighlightsTranslation in diverse noncoding regions is mitigated by proteasomal degradationC-terminal hydrophobicity is a hallmark of noncoding sequence derived polypeptidesA genome-wide CRISPR screen identified the BAG6 membrane protein triage pathwayRibosome-associated BAG6 complex targets C-terminal hydrophobicity for degradation

Intergenic regions of Saccharomycotina yeasts are enriched in potential to form transmembrane domains

“…Similarly, this enrichment could reflect evolutionary pressure to avoid expression of unwanted products, balanced against the advantage of occasionally allowing novelty to emerge. The overrepresentation of TM domains, perhaps coupled with the absence of other signals, could be part of a surveillance mechanism that detects and degrades aberrant translation products, similarly to what was found in a recent preprint 20 .…”

Intergenic Regions of Saccharomycotina Yeasts are Enriched in Potential to Encode Transmembrane Domains

“…Similarly, this enrichment could reflect evolutionary pressure to avoid expression of unwanted products, balanced against the advantage of occasionally allowing novelty to emerge. The overrepresentation of TM domains, perhaps coupled with the absence of other signals, could be part of a surveillance mechanism that detects and degrades aberrant translation products, similarly to what was found in a recent preprint ( Kesner et al 2022 ).…”

Massively integrated coexpression analysis reveals transcriptional regulation, evolution and cellular implications of the noncanonical translatome

“…Recent research in yeast has revealed a significant enrichment of transmembrane domains 16,22 (TMDs) within putative peptides of de novo ORFs, suggesting an association with cellular membranes. Notably, many studies identified de novo ORFs in yeast 22,59 and small nORFs in humans 14,67 that localize to diverse cellular membranes, such as ER, vacuole, endosome, or mitochondria. These findings have raised the possibility that de novo ORFs could play a role in a range of transport processes, such as ion, amino acid, and protein transport across cellular membranes.…”