Reduced Expression of Ribosomal Proteins Relieves MicroRNA-Mediated Repression

SummaryMicroRNAs (miRNAs) regulate physiological and pathological processes by inducing posttranscriptional repression of target messenger RNAs (mRNAs) via incompletely understood mechanisms. To discover factors required for human miRNA activity, we performed an RNAi screen using a reporter cell line of miRNA-mediated repression of translation initiation. We report that reduced expression of ribosomal protein genes (RPGs) dissociated miRNA complexes from target mRNAs, leading to increased polysome association, translation, and stability of miRNA-targeted mRNAs relative to untargeted mRNAs. RNA sequencing of polysomes indicated substantial overlap in sets of genes exhibiting increased or decreased polysomal association after Argonaute or RPG knockdowns, suggesting similarity in affected pathways. miRNA profiling of monosomes and polysomes demonstrated that miRNAs cosediment with ribosomes. RPG knockdowns decreased miRNAs in monosomes and increased their target mRNAs in polysomes. Our data show that most miRNAs repress translation and that the levels of RPGs modulate miRNA-mediated repression of translation initiation.

Graphical AbstractFigure optionsDownload high-quality image (106 K)Download as PowerPoint slideHighlights
► As a class ribosomal proteins (RPs) regulate miRNA-repressed translation initiation
► Reducing RPs decreases miRNAs in monosomes and shifts their targets to polysomes
► Nucleolar stress and p53 activation relieves miRNA-mediated repression
► miRNAs cosediment with ribosomes indicating widespread repression of translation