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Codon bias analysis of Zika virus (ZIKV) revealed slightly biased codon usage with a strong preference for codons ending with an adenine (A). This preference for nnA codons of the Zika genome while the human genome is biased towards codons ending by C or G (nnC, nnG), raises a potential problem for efficient viral translation, mainly when ribosomes will have to decode rare codons for the host and for which cognate tRNAs are under-represented in the pool or not properly modified at position U34 of the tRNA for wobble-based decoding. This is particularly the case for the Lys (AAA), Gln (CAA) and Glu (GAA) codons. Their decoding strictly depends on the presence of the mcm5s2 modification at position U34 of the corresponding tRNAs (tRNALysUUU; tRNAGlnUUG; tRNAGluUUC). Any mismatch between the codon usage of ZIKV and the tRNA pool of its cellular host could induce translation pauses, mistranslation and proteotoxic stress, which would be detrimental to the virus. Our results are based on (a) the use of codon-biased fluorescent sensors nnA or nnG for the 3 amino acids in question, (b) the analysis by mass spectrometry of the modifications of the tRNAs, and (c) the infection of human cells genetically incapable of performing the mcm5s2 modification at position U34 of their tRNAs. Our data clearly illustrate the ability of ZIKV to manipulate the pool of host tRNAs to facilitate its translation. In parallel, codon bias analysis of SARS-CoV-2 also revealed suboptimal codon adaptation in the context of human cells the virus infects. The precise examination of the codons preferentially used by SARS-CoV-2 shows a strong preference for the very same codons, requiring a modification of the U34 wobble position of the corresponding tRNAs (tLysUUU; tGlnUUG; tGluUUC) to be efficiently decoded. Collectively, our results bring to light a new paradigm according to which RNA viruses reprogram cellular tRNAs to maximize viral production.
Published on January 13, 2023