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N-terminal acetylation of the influenza ribonuclease PA-X promotes nuclear localization and host shutoff activity in a multifaceted manner.
bioRxiv 2023 December 3
To counteract host antiviral responses, influenza A virus triggers a global reduction of cellular gene expression, a process termed "host shutoff." A key effector of influenza A virus host shutoff is the viral endoribonuclease PA-X, which degrades host mRNAs. While many of the molecular determinants of PA-X activity remain unknown, a previous study identified a requirement for N-terminal acetylation of PA-X for its host shutoff activity, but did not address how this modification promotes activity. Here, we report that PA-X N-terminal acetylation has two functions that can be separated based on the position of the acetylation, on the first amino acid, i.e. the initiator methionine, vs. the second amino acid following initiator methionine excision. Modification at either site is sufficient to ensure correct PA-X localization to the nucleus. However, modification at the second amino acid is not sufficient for host shutoff activity of ectopically expressed PA-X, which requires N-terminal acetylation of the initiator methionine specifically. Interestingly, during infection, N-terminal acetylation of PA-X at any position results in PA-X host shutoff activity, and this is, in part, due to a functional interaction with the influenza protein NS1. This reveals an unexpected role for other viral proteins in PA-X activity. Our studies highlight the multifaceted nature of PA-X N-terminal acetylation in its ability to regulate the host shutoff activity of PA-X through multiple avenues.
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