IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-36389-0.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-36389-0
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-023-36389-0?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. 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.
    2. 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.
    3. 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.
    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.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Tomas Kouba & Dominik Vogel & Sigurdur R. Thorkelsson & Emmanuelle R. J. Quemin & Harry M. Williams & Morlin Milewski & Carola Busch & Stephan Günther & Kay Grünewald & Maria Rosenthal & Stephen Cusac, 2021. "Conformational changes in Lassa virus L protein associated with promoter binding and RNA synthesis activity," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    2. Jun Ma & Shuangyue Zhang & Xinzheng Zhang, 2021. "Structure of Machupo virus polymerase in complex with matrix protein Z," Nature Communications, Nature, vol. 12(1), pages 1-8, December.
    3. Alewo Idoko-Akoh & Daniel H. Goldhill & Carol M. Sheppard & Dagmara Bialy & Jessica L. Quantrill & Ksenia Sukhova & Jonathan C. Brown & Samuel Richardson & Ciara Campbell & Lorna Taylor & Adrian Sherm, 2023. "Creating resistance to avian influenza infection through genome editing of the ANP32 gene family," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    4. Benoît Arragain & Quentin Durieux Trouilleton & Florence Baudin & Jan Provaznik & Nayara Azevedo & Stephen Cusack & Guy Schoehn & Hélène Malet, 2022. "Structural snapshots of La Crosse virus polymerase reveal the mechanisms underlying Peribunyaviridae replication and transcription," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    5. Benoît Arragain & Tim Krischuns & Martin Pelosse & Petra Drncova & Martin Blackledge & Nadia Naffakh & Stephen Cusack, 2024. "Structures of influenza A and B replication complexes give insight into avian to human host adaptation and reveal a role of ANP32 as an electrostatic chaperone for the apo-polymerase," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36389-0. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.