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The ubiquitination landscape of the influenza A virus polymerase

Author

Listed:
  • Franziska Günl

    (University of Muenster
    University of Muenster)

  • Tim Krischuns

    (University of Muenster
    Institut Pasteur, Université Paris Cité, CNRS UMR3569, Unité Biologie des ARN et Virus Influenza)

  • Julian A. Schreiber

    (University of Muenster
    University Hospital Muenster)

  • Lea Henschel

    (University of Muenster)

  • Marius Wahrenburg

    (University of Muenster
    University Hospital Essen)

  • Hannes C. A. Drexler

    (Bioanalytical Mass Spectrometry, Max Planck Institute for Molecular Biomedicine)

  • Sebastian A. Leidel

    (University of Bern
    University of Bern)

  • Vlad Cojocaru

    (Max Planck Institute for Molecular Biomedicine
    Utrecht University
    Babeş-Bolyai University)

  • Guiscard Seebohm

    (University Hospital Muenster)

  • Alexander Mellmann

    (University of Muenster
    University of Muenster)

  • Martin Schwemmle

    (University Medical Center Freiburg
    University of Freiburg)

  • Stephan Ludwig

    (University of Muenster
    University of Muenster)

  • Linda Brunotte

    (University of Muenster
    University of Muenster)

Abstract

During influenza A virus (IAV) infections, viral proteins are targeted by cellular E3 ligases for modification with ubiquitin. Here, we decipher and functionally explore the ubiquitination landscape of the IAV polymerase proteins during infection of human alveolar epithelial cells by applying mass spectrometry analysis of immuno-purified K-ε-GG (di-glycyl)-remnant-bearing peptides. We have identified 59 modified lysines across the three subunits, PB2, PB1 and PA of the viral polymerase of which 17 distinctively affect mRNA transcription, vRNA replication and the generation of recombinant viruses via non-proteolytic mechanisms. Moreover, further functional and in silico analysis indicate that ubiquitination at K578 in the PB1 thumb domain is mechanistically linked to dynamic structural transitions of the viral polymerase that are required for vRNA replication. Mutations K578A and K578R differentially affect the generation of recombinant viruses by impeding cRNA and vRNA synthesis, NP binding as well as polymerase dimerization. Collectively, our results demonstrate that the ubiquitin-mediated charge neutralization at PB1-K578 disrupts the interaction to an unstructured loop in the PB2 N-terminus that is required to coordinate polymerase dimerization and facilitate vRNA replication. This provides evidence that IAV exploits the cellular ubiquitin system to modulate the activity of the viral polymerase for viral replication.

Suggested Citation

  • Franziska Günl & Tim Krischuns & Julian A. Schreiber & Lea Henschel & Marius Wahrenburg & Hannes C. A. Drexler & Sebastian A. Leidel & Vlad Cojocaru & Guiscard Seebohm & Alexander Mellmann & Martin Sc, 2023. "The ubiquitination landscape of the influenza A virus polymerase," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36389-0
    DOI: 10.1038/s41467-023-36389-0
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    References listed on IDEAS

    as
    1. Alexander Pflug & Delphine Guilligay & Stefan Reich & Stephen Cusack, 2014. "Structure of influenza A polymerase bound to the viral RNA promoter," Nature, Nature, vol. 516(7531), pages 355-360, December.
    2. Benjamin Mänz & Linda Brunotte & Peter Reuther & Martin Schwemmle, 2012. "Adaptive mutations in NEP compensate for defective H5N1 RNA replication in cultured human cells," Nature Communications, Nature, vol. 3(1), pages 1-11, January.
    3. Eiji Obayashi & Hisashi Yoshida & Fumihiro Kawai & Naoya Shibayama & Atsushi Kawaguchi & Kyosuke Nagata & Jeremy R. H. Tame & Sam-Yong Park, 2008. "The structural basis for an essential subunit interaction in influenza virus RNA polymerase," Nature, Nature, vol. 454(7208), pages 1127-1131, August.
    4. Stefan Reich & Delphine Guilligay & Alexander Pflug & Hélène Malet & Imre Berger & Thibaut Crépin & Darren Hart & Thomas Lunardi & Max Nanao & Rob W. H. Ruigrok & Stephen Cusack, 2014. "Structural insight into cap-snatching and RNA synthesis by influenza polymerase," Nature, Nature, vol. 516(7531), pages 361-366, December.
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