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<p>ADP-ribosylation is a highly dynamic and fully reversible post-translational modification performed by PARP enzymes that modulates protein function, abundance, localization, and turnover. Here we show that PARPs mount an antiviral response to influenza A virus infection causing a rapid and dramatic upregulation of global ADP-ribosylation that inhibits viral replication. Mass spectrometry analyzes define the global ADP-ribosylome during infection, creating an infection-specific profile with almost 4000 modification sites on ~1000 host proteins, as well as over 100 modification sites on viral proteins. Our data suggest that the global increase reflects a change in the form of ADP-ribosylation rather than modification of new targets. Functional assays demonstrate that modification of the viral replication machinery antagonizes its activity. We further show that the influenza A virus protein NS1 counteracts the anti-viral activity of PARPs and ADP-ribosylation, assigning a new activity to the primary viral antagonist of innate immunity. We identify PARP1 as the enzyme producing the majority of poly(ADP-ribose) present during infection. Influenza A virus replicates faster in cells lacking PARP1, linking PARP1 and ADP-ribosylation to the anti-viral phenotype. Together, these data establish ADP-ribosylation as an anti-viral innate immune-like response to viral infection antagonized by a previously unknown activity of NS1.</p>

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Global remodeling of ADP-ribosylation by PARP1 suppresses influenza A virus infection

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月17日

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  • Zhenyu Zhang,
  • Isabel Uribe,
  • Kaitlin A. Davis,
  • Robert L. McPherson,
  • Gloria P. Larson,
  • Mohsen Badiee,
  • Vy Tran,
  • Mitchell P. Ledwith,
  • Elizabeth M. Feltman,
  • Shuǐqìng Yú,
  • Yíngyún Caì,
  • Che-Yuan Chang,
  • Xingyi Yang,
  • Zhuo Ma,
  • Paul Chang,
  • Jens H. Kuhn,
  • Anthony K. L. Leung,
  • Andrew Mehle

摘要

ADP-ribosylation is a highly dynamic and fully reversible post-translational modification performed by PARP enzymes that modulates protein function, abundance, localization, and turnover. Here we show that PARPs mount an antiviral response to influenza A virus infection causing a rapid and dramatic upregulation of global ADP-ribosylation that inhibits viral replication. Mass spectrometry analyzes define the global ADP-ribosylome during infection, creating an infection-specific profile with almost 4000 modification sites on ~1000 host proteins, as well as over 100 modification sites on viral proteins. Our data suggest that the global increase reflects a change in the form of ADP-ribosylation rather than modification of new targets. Functional assays demonstrate that modification of the viral replication machinery antagonizes its activity. We further show that the influenza A virus protein NS1 counteracts the anti-viral activity of PARPs and ADP-ribosylation, assigning a new activity to the primary viral antagonist of innate immunity. We identify PARP1 as the enzyme producing the majority of poly(ADP-ribose) present during infection. Influenza A virus replicates faster in cells lacking PARP1, linking PARP1 and ADP-ribosylation to the anti-viral phenotype. Together, these data establish ADP-ribosylation as an anti-viral innate immune-like response to viral infection antagonized by a previously unknown activity of NS1.