Enterocytes are a necessary portal for fecal-oral transmission of viruses, including duck hepatitis A virus (DHAV), that act on the absorption of amino acids (AAs). We note that the rapid death of ducklings caused by DHAV is likely due to its rapid release from enterocytes. However, the underlying mechanism driving the release of DHAV remains poorly understood. Compared to infected fibroblasts, we found that DHAV-infected enterocytes triggered much more rapid viral release and induced swift and diverse remodeling of the mature tRNAome. Surprisingly, we found that tRNA-Ser-UGA in enterocytes was rapidly and specifically upregulated by DHAV infection and was highly correlated with serine decoding of DHAV, which is enriched with UCA codons. Overexpression of tRNA-Ser-UGA in enterocytes promoted rapid DHAV release, whereas overexpression of the cognate tRNA-Ser-GCU in enterocytes or the same tRNA in fibroblasts did not. In enterocytes, inhibition of serine charging of tRNA-Ser-UGA, transfection of a tRNAm-Ala-UGA backbone mutant or a tRNAm-Ser-UGA>CGA anticodon mutant decreased DHAV release. This finding suggests that tRNA-Ser-UGA plays a prominent role in DHAV release in infected enterocytes, which should be supported by efficient protein translation of the virus. Similarly, tRNA-Ser-UGA potently enhances DHAV protein synthesis, and the inhibition of charging of this tRNA or the transfection of the two mutants decreases DHAV protein synthesis. Phenotypically, the overexpression of tRNA-Ser-UGA in enterocytes further accelerates the spread of DHAV to hepatocytes. In conclusion, we revealed a novel tRNA-Ser-UGA that efficiently promotes the rapid release of DHAV by increasing serine decoding in infected enterocytes, thereby promoting remote cell-to-cell dissemination.
Keywords: Duck hepatitis A virus; Enterocytes; Gut‒liver axis; Virus release; tRNAome.
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