The interferon-inducible GTPase MxB promotes capsid disassembly and genome release of herpesviruses

  1. Manutea C Serrero
  2. Virginie Girault
  3. Sebastian Weigang
  4. Todd M Greco
  5. Ana Ramos Nascimento
  6. Fenja Anderson
  7. Antonio Piras
  8. Ana Hickford Martinez
  9. Jonny Hertzog
  10. Anne Binz
  11. Anja Pohlmann
  12. Ute Prank
  13. Jan Rehwinkel
  14. Rudolf Bauerfeind
  15. Ileana M Cristea
  16. Andreas Pichlmair
  17. Georg Kochs
  18. Beate Sodeik  Is a corresponding author
  1. Hannover Medical School, Germany
  2. Technical University of Munich, Germany
  3. University of Freiburg, Germany
  4. Princeton University, United States
  5. University of Oxford, United Kingdom

Abstract

Host proteins sense viral products and induce defence mechanisms, particularly in immune cells. Using cell-free assays and quantitative mass spectrometry, we determined the interactome of capsid-host protein complexes of herpes simplex virus and identified the large dynamin-like GTPase myxovirus resistance protein B (MxB) as an interferon-inducible protein interacting with capsids. Electron microscopy analyses showed that cytosols containing MxB had the remarkable capability to disassemble the icosahedral capsids of herpes simplex viruses and varicella zoster virus into flat sheets of connected triangular faces. In contrast, capsids remained intact in cytosols with MxB mutants unable to hydrolyse GTP or to dimerize. Our data suggest that MxB senses herpesviral capsids, mediates their disassembly, and thereby restricts the efficiency of nuclear targeting of incoming capsids and/or the assembly of progeny capsids. The resulting premature release of viral genomes from capsids may enhance the activation of DNA sensors, and thereby amplify the innate immune responses.

Data availability

The raw datasets produced in this study are available at PRIDE (PXD028276; http://www.ebi.ac.uk/pride). The dataset analyses and the raw bottling images are included in the Supplementary Files 1-3 and in the Source Data folder, respectively.

The following data sets were generated

Article and author information

Author details

  1. Manutea C Serrero

    Institute of Virology, Hannover Medical School, Hannover, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8221-2725
  2. Virginie Girault

    Institute of Virology, Technical University of Munich, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Sebastian Weigang

    Institute of Virology, University of Freiburg, Freiburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Todd M Greco

    Department of Molecular Biology, Princeton University, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Ana Ramos Nascimento

    Institute of Virology, Hannover Medical School, Hannover, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Fenja Anderson

    Institute of Virology, Hannover Medical School, Hannover, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Antonio Piras

    Institute of Virology, Technical University of Munich, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Ana Hickford Martinez

    Institute of Virology, Hannover Medical School, Hannover, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Jonny Hertzog

    MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7089-982X
  10. Anne Binz

    Institute of Virology, Hannover Medical School, Hannover, Germany
    Competing interests
    The authors declare that no competing interests exist.
  11. Anja Pohlmann

    Institute of Virology, Hannover Medical School, Hannover, Germany
    Competing interests
    The authors declare that no competing interests exist.
  12. Ute Prank

    Institute of Virology, Hannover Medical School, Hannover, Germany
    Competing interests
    The authors declare that no competing interests exist.
  13. Jan Rehwinkel

    MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  14. Rudolf Bauerfeind

    Institute of Virology, Hannover Medical School, Hannover, Germany
    Competing interests
    The authors declare that no competing interests exist.
  15. Ileana M Cristea

    Department of Molecular Biology, Princeton University, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Andreas Pichlmair

    Institute of Virology, Technical University of Munich, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0166-1367
  17. Georg Kochs

    Institute of Virology, University of Freiburg, Freiburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  18. Beate Sodeik

    Institue of Virology, Hannover Medical School, Hannover, Germany
    For correspondence
    sodeik.beate@mh-hannover.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4650-3036

Funding

Horizon 2020 Framework Programme (H2020-EU.1.3.1)

  • Jan Rehwinkel
  • Andreas Pichlmair
  • Beate Sodeik

Medical Research Council

  • Jan Rehwinkel

National Institutes of Health (NIGMS,GM114141)

  • Ileana M Cristea

European Research Council (ERC-CoG ProDAP 817798)

  • Andreas Pichlmair

Deutsche Forschungsgemeinschaft (PI1084/3,PI1084/4,PI1084/5,TRR179,and TRR237)

  • Andreas Pichlmair

Deutsche Forschungsgemeinschaft (KO1579/13)

  • Georg Kochs

Deutsche Forschungsgemeinschaft (CRC900 C2 158989968,EXC62 REBIRTH 24102914,EXC2155 RESIST 390874280,SO403/6)

  • Beate Sodeik

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Adam P Geballe, Fred Hutchinson Cancer Research Center, United States

Publication history

  1. Received: January 5, 2022
  2. Preprint posted: January 27, 2022 (view preprint)
  3. Accepted: April 22, 2022
  4. Accepted Manuscript published: April 27, 2022 (version 1)

Copyright

© 2022, Serrero et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Manutea C Serrero
  2. Virginie Girault
  3. Sebastian Weigang
  4. Todd M Greco
  5. Ana Ramos Nascimento
  6. Fenja Anderson
  7. Antonio Piras
  8. Ana Hickford Martinez
  9. Jonny Hertzog
  10. Anne Binz
  11. Anja Pohlmann
  12. Ute Prank
  13. Jan Rehwinkel
  14. Rudolf Bauerfeind
  15. Ileana M Cristea
  16. Andreas Pichlmair
  17. Georg Kochs
  18. Beate Sodeik
(2022)
The interferon-inducible GTPase MxB promotes capsid disassembly and genome release of herpesviruses
eLife 11:e76804.
https://doi.org/10.7554/eLife.76804

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