tetano
Editor, Senior Moderator
Nat Commun
. 2025 Dec 17;16(1):11176.
doi: 10.1038/s41467-025-66136-6. Global remodeling of ADP-ribosylation by PARP1 suppresses influenza A virus infection
Zhenyu Zhang[SUP] #[/SUP][SUP] 1 [/SUP], Isabel Uribe[SUP] #[/SUP][SUP] 2 [/SUP], Kaitlin A Davis[SUP] 1 [/SUP], Robert L McPherson[SUP] 2 [/SUP], Gloria P Larson[SUP] 1 [/SUP], Mohsen Badiee[SUP] 2 [/SUP], Vy Tran[SUP] 1 [/SUP], Mitchell P Ledwith[SUP] 1 [/SUP], Elizabeth M Feltman[SUP] 1 [/SUP], Shuǐqìng Yú[SUP] 3 [/SUP], Yíngyún Caì[SUP] 3 [/SUP], Che-Yuan Chang[SUP] 2 [/SUP], Xingyi Yang[SUP] 2 [/SUP], Zhuo Ma[SUP] 2 [/SUP], Paul Chang[SUP] 4 5 6 [/SUP], Jens H Kuhn[SUP] 3 [/SUP], Anthony K L Leung[SUP] 7 8 9 10 [/SUP], Andrew Mehle[SUP] 11 [/SUP]
Affiliations
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.
. 2025 Dec 17;16(1):11176.
doi: 10.1038/s41467-025-66136-6. Global remodeling of ADP-ribosylation by PARP1 suppresses influenza A virus infection
Zhenyu Zhang[SUP] #[/SUP][SUP] 1 [/SUP], Isabel Uribe[SUP] #[/SUP][SUP] 2 [/SUP], Kaitlin A Davis[SUP] 1 [/SUP], Robert L McPherson[SUP] 2 [/SUP], Gloria P Larson[SUP] 1 [/SUP], Mohsen Badiee[SUP] 2 [/SUP], Vy Tran[SUP] 1 [/SUP], Mitchell P Ledwith[SUP] 1 [/SUP], Elizabeth M Feltman[SUP] 1 [/SUP], Shuǐqìng Yú[SUP] 3 [/SUP], Yíngyún Caì[SUP] 3 [/SUP], Che-Yuan Chang[SUP] 2 [/SUP], Xingyi Yang[SUP] 2 [/SUP], Zhuo Ma[SUP] 2 [/SUP], Paul Chang[SUP] 4 5 6 [/SUP], Jens H Kuhn[SUP] 3 [/SUP], Anthony K L Leung[SUP] 7 8 9 10 [/SUP], Andrew Mehle[SUP] 11 [/SUP]
Affiliations
- PMID: 41407686
- PMCID: PMC12711997
- DOI: 10.1038/s41467-025-66136-6
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.