Coronaviruses reprogram the tRNA epitranscriptome to favor viral protein expression

TL;DR

Coronaviruses alter tRNA modifications to improve their protein production despite using inefficient codons, which could be a target for antiviral therapies.

Contribution

The study identifies specific tRNA modifications reprogrammed by coronaviruses to enhance viral protein expression.

Findings

SARS-CoV-2 and HCoV-OC43 reprogram tRNA modifications to decode suboptimal codons efficiently.

The reprogramming is driven by altered expression of tRNA modifying enzymes.

The modifications align with stress-induced changes that favor stress response protein expression.

Abstract

Coronaviruses genomes are enriched in suboptimal A- and U-ending codons, which are typically associated with reduced translation efficiency due to limited cognate tRNA availability. How coronavirus efficiently express their proteins despite this limitation remains unclear. By analyzing their codon usage, we identify four tRNA modifications—inosine (I), queuosine (Q), 5-methylcarboxymethyluridine/ 5-methylcarboxymethyl-2-thiouridine (mcm5U/mcm5s2U), and 5-methylcytidine/ 5-formylcytidine (m5C/f5C)—as essential for decoding their suboptimal codons. Notably, SARS-CoV-2 and HCoV-OC43 infections, representing severe and mild human infections, respectively, reprogram these modifications to favor viral protein synthesis. Mechanistically, this reprogramming was driven by altered expression of the corresponding tRNA modifying enzymes. Since both viruses induced DNA damage and oxidative stress—known to similarly alter Q, mcm5U/mcm5s2U, and m5C/f5C modifications to favor expression of stress response proteins—our findings support that coronavirus genomes have adapted to the tRNA modification landscape under stress conditions. Overall, coronaviruses orchestrate a codon-specific reprogramming of the host tRNA modification landscape, highlighting a conserved strategy that optimizes translation efficiency and represents a promising target for pan-coronavirus antiviral therapy development.

Coronaviruses use suboptimal codons yet efficiently translate proteins. Here, the authors show that SARS-CoV-2 and HCoV-OC43 infections reprogram four host tRNA modifications, linking stress-induced tRNA remodelling to enhanced viral translation.

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