The synergistic effect of residues 32T and 550L in the PA protein of H5 subtype avian influenza virus contributes to viral pathogenicity in mice

The avian influenza virus (AIV) PA protein contributes to viral replication and pathogenicity; however, its interaction with innate immunity is not well understood. Here, we report that the H5 subtype AIV PA protein strongly suppresses host antiviral defense by interacting with and degrading a key protein in interferon (IFN) signaling, Janus kinase 1 (JAK1). Specifically, the AIV PA protein catalyzes the K48-linked polyubiquitination and degradation of JAK1 at lysine residue 249. Importantly, the AIV PA protein harboring 32T/550L degrades both avian and mammalian JAK1, while the AIV PA protein with residues 32M/550I degrades avian JAK1 only. Furthermore, the residues 32T/550L in PA protein confer optimum polymerase activity and AIV growth in mammalian cells. Notably, the replication and virulence of the AIV PA T32M/L550I mutant are attenuated in infected mice. Collectively, these data reveal an interference role for H5 subtype AIV PA protein in host innate immunity, which can be targeted for the development of specific and effective anti-influenza therapeutics. Author summaryThe highly pathogenic avian influenza virus (HPAIV) circulates in several countries and causes multiple human infections worldwide. In the present study, we found that two novel residues 32T and 550L in the PA protein of AIV inhibit the IFN-mediated immune response by diminishing JAK1 protein levels and maintaining optimum polymerase activity in mammalian cells. We further revealed that the two amino acids were responsible for the pathogenicity of H5 HPAIV in infected mice. Our study emphasizes the importance of PA protein in the increased pathogenicity of HPAIV and provides important insights for understanding the molecular mechanisms of virus-host interactions, which are critical for developing control strategies for HPAIV.

Automated summary

The H5 subtype avian influenza virus (AIV) PA protein suppresses host antiviral defense by degrading the key protein JAK1 involved in interferon signaling. Mutations in the PA protein contribute to the pathogenicity of the virus in both avian and mammalian hosts. These findings provide insights into the molecular mechanisms of virus-host interactions and potential therapeutic targets for controlling avian influenza.