2. Academic Validation
  3. Global remodeling of ADP-ribosylation by PARP1 suppresses influenza A virus infection

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

  • bioRxiv. 2024 Sep 19:2024.09.19.613696. doi: 10.1101/2024.09.19.613696.
Zhenyu Zhang 1,  Isabel Uribe 2,  Kaitlin A Davis 1,  Robert Lyle McPherson 2,  Gloria P Larson 1,  Mohsen Badiee 2,  Vy Tran 1,  Mitchell P Ledwith 1,  Elizabeth Feltman 1,  Shuǐqìng Yú 3,  Yíngyún Caì 3,  Che-Yuan Chang 2,  Xingyi Yang 2,  Zhuo Ma 2,  Paul Chang 4 5,  Jens H Kuhn 3,  Anthony K L Leung 2 6 7 8,  Andrew Mehle 1 9
Affiliations

Affiliations

  • 1 Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, WI.
  • 2 Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
  • 3 Integrated Research Facility at Fort Detrick, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick, Frederick, MD, USA.
  • 4 Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 5 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 6 Department of Molecular Biology and Genetics, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
  • 7 Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
  • 8 Department of Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
  • 9 Lead Contact.
PMID: 39345583 DOI: 10.1101/2024.09.19.613696
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.

Keywords

ADP-ribosylation; ELTA-MS; NS1; PARP; PARP1; PARylation; influenza A virus; poly(ADP-ribose) polymerases; poly(ADP-ribosyl)ation.

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