Translation is a key determinant controlling the fate of cytoplasmic long non-coding RNAs

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Abstract
Despite being predicted to lack coding potential, cytoplasmic long non-coding (lnc)RNAs can associate with ribosomes, which may result in the production of functional peptides. However, the landscape and biological relevance of lncRNAs translation remains poorly studied. In the budding yeast Saccharomyces cerevisiae , cytoplasmic Xrn1-sensitive lncRNAs (XUTs) are targeted by the Nonsense-Mediated mRNA Decay (NMD), suggesting a translation-dependent degradation process. Here, we report that XUTs are translated, which impacts their abundance. We show that XUTs globally accumulate upon translation elongation inhibition, but not when initial ribosome loading is impaired. Translation also affects XUTs independently of NMD, in some cases interfering with their decapping. Ribo-Seq confirmed ribosomes binding to XUTs and identified actively translated small ORFs in their 5’-proximal region. Mechanistic analyses revealed that their NMD-sensitivity mainly depends on the 3’-untranslated region length. Finally, we detected the peptide derived from the translation of an NMD-sensitive XUT reporter in NMD-competent cells. Our work highlights the role of translation in the post-transcriptional metabolism of XUTs, acting as a modulator of their expression. We propose that XUT-derived peptides could be exposed to the natural selection, while NMD restricts XUTs levels.
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