Year: 2025
Type: article
Abstract: ADP-ribosylation is a highly dynamic and fully reversible post-translational modification performed by poly(ADP-ribose) polymerases (PARPs) that modulates protein function, abundance, localization and turnover. Here we show that influenza A virus infection causes a rapid and dramatic upregulation of global ADP-ribosylation that inhibits viral replication. Mass spectrometry defined for the first time the global ADP-ribosylome during infection, creating an infection-specific profile with almost 4,300 modification sites on ~1,080 host proteins, as well as over 100 modification sites on viral proteins. Our data indicate that the global increase likely reflects a change in the form of ADP-ribosylation rather than modification of new targets. Functional assays demonstrated that modification of the viral replication machinery antagonizes its activity and further revealed that the anti-viral activity of PARPs and ADP-ribosylation is counteracted by the influenza A virus protein NS1, assigning a new activity to the primary viral antagonist of innate immunity. We identified PARP1 as the enzyme producing the majority of poly(ADP-ribose) present during infection. Influenza A virus replicated 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.
Source: Nature Communications
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: National Science Foundation, U.S. Department of Defense, U.S. Department of Health and Human Services, Burroughs Wellcome Fund, Battelle, Wisconsin Alumni Research Foundation, University of Wisconsin-Madison, Johns Hopkins University, National Institutes of Health, Office of the Vice Chancellor for Research and Graduate Education, University of Wisconsin-Madison, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases
Awards: Graduate Research Fellowship Program (GRFP), G1156098453, G1254506003, G1740777501, Regulation of the influenza virus polymerase, G2104295115, G2377973497, G2613132665, G2657606753, G2997799923, Fourier Transform Orbitrap Fusion Lumos Tribrid Mass Spectrometer with ETD, G3181926206, G3343527953, G3622839095, G3690347603, G3804967477, G3980900660, G485454578, G5682192841, G5958748597, RNA:protein interactions that dictate the success of influenza virus infection, G6670064158, G6726236015, Graduate Training in Molecular Biosciences, G680755831, G7127658568, G7177776953, Virology Training Grant, Dissecting ADP-ribosylation as an innate immune response countering influenza virus replication, G7282392797, G7569237983, Developing Mass Spectrometry-based Approaches to Characterize Mono- and Poly(ADP-ribosyl)ated Proteomes, G8990813452, Training in Areas Fundamental to Cancer Research
OpenAlex ID: W4417423953