Key result
The influenza A virus host shutoff factor PA-X is rapidly turned over in a strain-specific manner, with half-lives ranging from approximately 30 minutes to 3.5 hours depending on the viral strain.
Why the study?
Despite its role in regulating virulence and host gene expression, PA-X protein levels remain markedly low during influenza A virus infection, and how PA-X is regulated post-translationally remains unknown.
The influenza A virus host shutoff factor PA-X is rapidly turned over in a strain-specific manner, suggesting protein stability is a mechanism to regulate its activity and viral virulence.
Strain-specific PA-X turnover suggests a virulence mechanism in animal models; human relevance remains undetermined.
The influenza A endoribonuclease PA-X regulates virulence and transmission of the virus by reducing host gene expression and thus regulating immune responses to influenza A virus. Despite this key function in viral biology, the levels of PA-X protein remain markedly low during infection, and previous results suggest that these low levels are not solely the result of regulation of the level of translation and RNA stability. How PA-X is regulated post-translationally remains unknown. We now report that the PA-X protein is rapidly turned over. PA-X from multiple viral strains are short-lived, although the half-life of PA-X ranges from ∼30 minutes to ∼3.5 hours depending on the strain. Moreover, sequences in the variable PA-X C-terminal domain are primarily responsible for regulating PA-X half-life, although the N-terminal domain also accounts for some differences among strains. Interestingly, we find that the PA-X from the 2009 pandemic H1N1 strain has a longer half-life compared to the other variants we tested. This PA-X isoform has been reported to have a higher host shutoff activity, suggesting a role for protein turnover in regulating PA-X activity. Collectively, this study reveals a novel regulatory mechanism of PA-X protein levels that may impact host shutoff activity during influenza A virus infection. IMPORTANCE The PA-X protein from influenza A virus reduces host immune responses to infection through suppressing host gene expression, including genes encoding the antiviral response. Thus, it plays a central role in influenza A virus biology. Despite its key function, PA-X was only discovered in 2012 and much remains to be learned including how PA-X activity is regulated to promote optimal levels of viral infection. In this study, we reveal that PA-X protein levels are very low likely because of rapid turnover. We show that instability is a conserved property among PA-X variants from different strains of influenza A virus, but that the half-lives of PA-X variants differ. Moreover, the longer half-life of PA-X from the 2009 pandemic H1N1 strain correlates with its reported higher activity. Therefore, PA-X stability may be a way to regulate its activity and may contribute to the differential virulence of influenza A virus strains.
No takes yet. Share an insight, caveat, or question.
Levene et al. (2020) studied Influenza A virus infection. Influenza A virus PA-X protein variants was evaluated on PA-X protein half-life. The influenza A virus host shutoff factor PA-X is rapidly turned over in a strain-specific manner, with half-lives ranging from approximately 30 minutes to 3.5 hours depending on the viral strain.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: