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

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. Massively parallel reporter assays for the translation of noncoding sequences in HEK293T cells and BAG6 KO cells

翻译过程广泛存在于经典编码区之外，可发生于长链非编码RNA（lncRNAs）、非翻译区（UTRs）以及内含子中。尽管由此产生的多肽通常不具备功能，但非编码区的翻译仍是新编码区诞生的必要条件。目前尚不清楚针对不同非编码区翻译的监控机制，以及逃逸监控的多肽如何演化出新功能。有趣的是，源自非编码序列的功能性多肽通常会定位于膜结构。本研究发现，非编码基因组与遗传密码中的固有核苷酸偏好性，常会催生带有疏水C端尾段的多肽；这类多肽会被核糖体结合的BAG6膜蛋白分选复合物识别捕获，随后被引导至蛋白酶体降解或膜靶向途径。与之相反，经典蛋白质在演化过程中已逐步剔除C端疏水氨基酸残基。本研究结果揭示了一套针对不同非编码区异常翻译的容错监控机制，并为新演化蛋白质优先定位于膜结构提供了一种潜在的生化途径。本研究针对人胚肾293T（HEK293T）细胞与BAG6基因敲除细胞中的非编码序列翻译，开展了大规模平行报告基因实验。