Dual signaling via interferon and DNA damage response elicits entrapment by giant PML nuclear bodies

  1. Myriam Scherer
  2. Clarissa Read
  3. Gregor Neusser
  4. Christine Kranz
  5. Anna K Kuderna
  6. Regina Müller
  7. Florian Full
  8. Sonja Woerz
  9. Anna Reichel
  10. Eva-Maria Schilling
  11. Paul Walther
  12. Thomas Stamminger  Is a corresponding author
  1. Ulm University Medical Center, Germany
  2. ULM University, Germany
  3. Friedrich Alexander Universität Erlangen-Nürnberg, Germany

Abstract

PML nuclear bodies (PML-NBs) are dynamic interchromosomal macromolecular complexes implicated in epigenetic regulation as well as antiviral defense. During herpesvirus infection, PML-NBs induce epigenetic silencing of viral genomes, however, this defense is antagonized by viral regulatory proteins such as IE1 of human cytomegalovirus (HCMV). Here, we show that PML-NBs undergo a drastic rearrangement into highly enlarged PML cages upon infection with IE1-deficient HCMV. Importantly, our results demonstrate that dual signaling by interferon and DNA damage response is required to elicit giant PML-NBs. DNA labeling revealed that invading HCMV genomes are entrapped inside PML-NBs and remain stably associated with PML cages in a transcriptionally repressed state. Intriguingly, by correlative light and transmission electron microscopy (EM), we observed that PML cages also entrap newly assembled viral capsids demonstrating a second defense layer in cells with incomplete first line response. Further characterization by 3D EM showed that hundreds of viral capsids are tightly packed into several layers of fibrous PML. Overall, our data indicate that giant PML-NBs arise via combined interferon and DNA damage signaling which triggers entrapment of both nucleic acids and proteinaceous components. This represents a multilayered defense strategy to act in a cytoprotective manner and to combat viral infections.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figures 1, 3, 4, 5, 6 and Figure 5-figure supplement 2

Article and author information

Author details

  1. Myriam Scherer

    Institute of Virology, Ulm University Medical Center, Ulm, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Clarissa Read

    Central Facility for Electron Microscopy, ULM University, Ulm, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Gregor Neusser

    Institute of Analytical and Bioanalytical Chemistry, ULM University, Ulm, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Christine Kranz

    Institute of Analytical and Bioanalytical Chemistry, ULM University, Ulm, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Anna K Kuderna

    Institute of Virology, Ulm University Medical Center, Ulm, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Regina Müller

    Institute of Clinical and Molecular Virology, Friedrich Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Florian Full

    Institute of Clinical and Molecular Virology, Friedrich Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Sonja Woerz

    Institute of Virology, Ulm University Medical Center, Ulm, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Anna Reichel

    Institute of Virology, Ulm University Medical Center, Ulm, Germany
    Competing interests
    The authors declare that no competing interests exist.
  10. Eva-Maria Schilling

    Institute of Virology, Ulm University Medical Center, Ulm, Germany
    Competing interests
    The authors declare that no competing interests exist.
  11. Paul Walther

    Central Facility for Electron Microscopy, ULM University, Ulm, Germany
    Competing interests
    The authors declare that no competing interests exist.
  12. Thomas Stamminger

    Institute of Virology, Ulm University Medical Center, Ulm, Germany
    For correspondence
    thomas.stamminger@uni-ulm.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9878-3119

Funding

Deutsche Forschungsgemeinschaft (STA357/7-1)

  • Thomas Stamminger

Deutsche Forschungsgemeinschaft (STA357/8-1)

  • Thomas Stamminger

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

Reviewing Editor

  1. Melanie M Brinkmann, Technische Universität Braunschweig, Germany

Version history

  1. Received: August 12, 2021
  2. Preprint posted: August 26, 2021 (view preprint)
  3. Accepted: March 23, 2022
  4. Accepted Manuscript published: March 23, 2022 (version 1)
  5. Version of Record published: April 1, 2022 (version 2)

Copyright

© 2022, Scherer 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. Myriam Scherer
  2. Clarissa Read
  3. Gregor Neusser
  4. Christine Kranz
  5. Anna K Kuderna
  6. Regina Müller
  7. Florian Full
  8. Sonja Woerz
  9. Anna Reichel
  10. Eva-Maria Schilling
  11. Paul Walther
  12. Thomas Stamminger
(2022)
Dual signaling via interferon and DNA damage response elicits entrapment by giant PML nuclear bodies
eLife 11:e73006.
https://doi.org/10.7554/eLife.73006

Share this article

https://doi.org/10.7554/eLife.73006

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