Virus-induced codon-specific reprogramming to favor viral RNA translation

How viruses, such as the emerging mosquito-borne Chikungunya virus (CHIKV), express their genomes at high levels despite an enrichment in suboptimal codons remains a puzzling question. By integrating subcellular fractionation and transcriptome-wide analyses of translation in CHIKV-infected human cells, we demonstrate an unanticipated virus-induced reprogramming of the host translation machinery to favor translation of viral RNA over cellular genes featuring optimal codon usage. This reprogramming was specifically apparent at the endoplasmic reticulum (ER), the preferred translation compartment of CHIKV RNA, and it is mediated by the wobble uridine 34 tRNA modification enzyme KIAA1456 whose expression is enhanced upon viral infection. Since KIAA1456 itself is encoded by a CHIKV-like codon usage, infection triggers a positive feed-back loop that ensures efficient virus protein production. Our findings demonstrate an unprecedented interplay of viruses with the host tRNA epitranscriptome to favor viral protein expression. Overall design: HEK 293T cells were subjected to subcellular fractionation after being infected with Chikungunya virus for 12 h (MOI=40), while control cells were mock infected for 12 h. Both subcellular compartments were then subjected to RNA-seq and Ribo-seq to identify differentially translated mRNAs. All experiments were performed at least in triplicates.