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Translational remodeling by RNA‐binding proteins and noncoding RNAs

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Abstract Responsible for generating the proteome that controls phenotype, translation is the ultimate convergence point for myriad upstream signals that influence gene expression. System‐wide adaptive translational reprogramming has recently emerged as a pillar of cellular adaptation. As classic regulators of mRNA stability and translation efficiency, foundational studies established the concept of collaboration and competition between RNA‐binding proteins (RBPs) and noncoding RNAs (ncRNAs) on individual mRNAs. Fresh conceptual innovations now highlight stress‐activated, evolutionarily conserved RBP networks and ncRNAs that increase the translation efficiency of populations of transcripts encoding proteins that participate in a common cellular process. The discovery of post‐transcriptional functions for long noncoding RNAs (lncRNAs) was particularly intriguing given their cell‐type‐specificity and historical definition as nuclear‐functioning epigenetic regulators. The convergence of RBPs, lncRNAs, and microRNAs on functionally related mRNAs to enable adaptive protein synthesis is a newer biological paradigm that highlights their role as “translatome (protein output) remodelers” and reinvigorates the paradigm of “RNA operons.” Together, these concepts modernize our understanding of cellular stress adaptation and strategies for therapeutic development. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein‐RNA Interactions: Functional Implications Translation > Translation Regulation Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs
Oxygen‐dependent refocusing of RBP‐regulated cellular pathways. Hypoxia‐sensitive RBPs PCBP1, hnRNP A2/B1, HuR, PCBP2, and PTBP1 constitute a translatome remodeling network that enhances the translation efficiency of mRNAs involved in hypoxia‐adaptive pathways (blue) including glycolysis and protein folding. These RBPs regulate different pathways under standard growth (normoxia) conditions (red), and the hypoxic “switch” in their target mRNAs/processes is dependent on the hypoxia‐inducible factor HIF‐2α. Some pathways continue to be regulated by these RBPs regardless of changes in oxygen availability (gray). ECM, extracellular matrix. Translational maintenance includes ribosomal protein synthesis, ribosomal RNA processing, assembly of ribosomes and translation initiation and preinitiation complexes, and tRNA aminoacylation
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High throughput approaches for translatome analysis. (a) Schematic of MATRIX, a proteomic technique to unbiasedly assess the cellular translational architecture. See main text for details. (b) RNA sequencing of ribosome density fractions provides a parallel means of comparing lncRNA translatome remodeling activities with that of their protein counterparts for example, RBPs. Additional techniques including proteomic translatome analysis, RNA footprinting, and in vitro translation assays will help distinguish protein synthesis regulatory activities of lncRNAs from their role as templates for translation
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Dynamic regulation of RNA regulons by translatome remodeling RBPs and lncRNAs. In response to physiological or pharmacological stimuli, RBPs and lncRNAs can coordinately increase the translational efficiency of mRNA populations (RNA regulons) that encode functionally related proteins for stimuli adaptation. They achieve this in part by regulating the differential recruitment of specific mRNAs to the translation machinery. LncRNAs can also function as decoys for translation‐inhibiting RBPs and microRNAs, and also promote adaptation through protein stabilization. RBPs and lncRNAs can also down‐regulate the translation efficiency of mRNAs with lesser stress‐adaptive value. In contrast to microRNAs which function almost exclusively as translation inhibitors, lncRNAs (like RBPs) can either promote or repress mRNA translation efficiency
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Diversity of STEEL RNPs. The endothelial‐enriched lncRNA STEEL is detectable in both the nucleus and cytoplasm. Biotinylated RNA pull‐downs revealed STEEL‐associated proteins with diverse cellular functions. (a) STEEL has been shown to mediate transcriptional regulation and epigenetic changes by recruiting nuclear proteins such as PARP1 to the promoters of target genes such as KLF2 (Kruppel‐like factor 2) and eNOS (endothelial nitric oxide synthase). STEEL also interacts with nuclear/cytoplasmic shuttling RBPs, which together with its detectable cytoplasmic presence suggest that STEEL also engages in cytoplasmic activities that include translation and microRNA regulation. (b) STEEL‐interacting proteins include those for example, hnRNP A1, DHX9, and ILF3 with nuclear/cytoplasmic shuttling and cytoplasmic functions, in addition to those with known nuclear activities for example, PARP1, MECP2, and H1.1
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Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs
Translation > Translation Regulation
RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications

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