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Article Abstract
RPS3, a universal core component of the 40S ribosomal subunit, interacts with mRNA at the entry channel. Whether RPS3 mRNA-binding contributes to specific mRNA translation and ribosome specialization in mammalian cells is unknown. Here we mutated RPS3 mRNA-contacting residues R116, R146 and K148 and report their impact on cellular and viral translation. R116D weakened cap-proximal initiation and promoted leaky scanning, while R146D had the opposite effect. Additionally, R146D and K148D displayed contrasting effects on start-codon fidelity. Translatome analysis uncovered common differentially translated genes of which the downregulated set bears long 5'UTR and weak AUG context, suggesting a stabilizing role during scanning and AUG selection. We identified an RPS3-dependent regulatory sequence (RPS3RS) in the sub-genomic 5'UTR of SARS-CoV-2 consisting of a CUG initiation codon and a downstream element that is also the viral transcription regulatory sequence (TRS). Furthermore, RPS3 mRNA-binding residues are essential for SARS-CoV-2 NSP1-mediated inhibition of host translation and for its ribosomal binding. Intriguingly, NSP1-induced mRNA degradation was also reduced in R116D cells, indicating that mRNA decay occurs in the ribosome context. Thus, RPS3 mRNA-binding residues have multiple translation regulatory functions and are exploited by SARS-CoV-2 in various ways to influence host and viral mRNA translation and stability.
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| http://dx.doi.org/10.1093/nar/gkad269 | DOI Listing |
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Selective translational control of cellular and viral mRNAs by RPS3 mRNA binding.
Nucleic Acids Res
May 2023
Dept. of Biomolecular Sciences, The Weizmann Institute of Science, Rehovot 7610001, Israel.
Article Synopsis
- * Mutations in specific residues of RPS3 (R116, R146, and K148) revealed differing impacts on translation initiation, start-codon accuracy, and gene translation patterns, especially for mRNAs with long 5'UTRs.
- * RPS3's interaction with mRNA is crucial for SARS-CoV-2's ability to inhibit host translation and its mRNA stability, highlighting its role in viral manipulation of host cellular mechanisms.
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