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.

中文翻译：

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甲型流感病毒宿主的封闭核糖核酸内切酶PA-X的C末端结构域在介导PA-X蛋白快速周转中的新作用

甲型流感病毒核糖核酸内切酶PA-X通过减少宿主基因的表达从而调节对甲型流感病毒的免疫应答来调节病毒的毒力和传播。尽管在病毒生物学中起着关键作用，但在感染过程中PA-X蛋白的水平仍然很低，以前的结果表明，这些低水平不仅是翻译水平和RNA稳定性调节的结果。翻译后如何调控PA-X仍然未知。现在，我们报告PA-X蛋白被快速翻转。尽管来自不同菌株的PA-X的半衰期有所不同，范围从30分钟到几小时不等，但在多个病毒株中仍可保持这种不稳定性。此外，可变PA-X C末端结构域中的序列调节PA-X半衰期。有趣的是 我们发现，与我们测试的其他变体相比，2009年大流行H1N1菌株的PA-X具有更长的半衰期。据报道该PA-X同工型具有较高的宿主关闭活性，表明蛋白质更新在调节PA-X活性中起作用。总的来说，这项研究揭示了一种可能影响甲型流感病毒感染期间宿主关闭活性的PA-X蛋白水平的新型调节机制。