Impact of influenza PA-X on host response

Influenza virus infection causes global shutdown of host protein synthesis in the infected cells, while viral proteins are efficiently produced. This host shutoff activity is considered to allow the virus to escape host innate and acquired immune recognition, which otherwise restricts viral replication and spread. It had been thought that cap snatching activity and degradation of host RNA polymerase II induced by viral RNA polymerase cause host shutoff [1,2]. However, a recent study revealed that influenza A virus expresses an additional viral protein, PA-X that plays a major role in suppression of host protein synthesis in infected cells [3]. PA-X encodes N-terminal 191 amino acids of PA protein and unique C-terminal sequences (41 or 61 amino acid residues) produced by +1 reading frame of PA mRNA via ribosomal frameshifting [3]. PA-X contains endonuclease active domain in its N-terminal region that is common to the PA protein. We and Jagger et al., demonstrated that transfection of a PA-X variant containing a single mutation at the endonuclease active site failed to suppress production of co-expressed reporter proteins, indicating that PA-X suppresses host protein synthesis via mRNA decay [3,4]. Although both PA and PA-X have identical endonuclease active site in their N-terminal domain, PA-X induced much stronger host shutoff activity than PA, suggesting an important role of unique C-terminal region of PA-X in host shutoff [3,4]. A recent report indicates that six basic amino acid residues within the N-terminal 15 residues of PA-X-unique region played a role in the optimal shutoff activity [5]. These basic residues are highly conserved among influenza A viruses, suggesting their essential role in effective shutoff activity [5]. PA-X activities in host shutoff vary among strains. Residues within the common N-terminal domain reflected the difference in PA-X activity [4]. Interestingly, PA-X from avian viruses was more active than that of human viruses, which might suggest a role of PA-X in optimal growth in their specific hosts [4]. To analyze the effect of PA-X of currently circulating viruses on virus growth and pathogenicity, we recently rescued a mutant 2009 pandemic H1N1 virus (pH1N1) expressing reduced amount of PA-X through mutations at the frameshift motif (PA-XFS) [6]. In agreement with the results using 1918 highly pathogenic influenza A virus [3], pH1N1 PA-X degrades host mRNA and suppresses host protein synthesis in infected cells [6]. Unlike 1918 PA-XFS, however, pH1N1 PA-XFS was attenuated both in cultured human cells and the infected mouse …