Ribosome biogenesis restricts innate immune responses to virus infection and DNA

  1. Christopher Bianco
  2. Ian Mohr  Is a corresponding author
  1. NYU School of Medicine, United States

Abstract

Ribosomes are universally important in biology and their production is dysregulated by developmental disorders, cancer, and virus infection. Although presumed required for protein synthesis, how ribosome biogenesis impacts virus reproduction and cell-intrinsic immune responses remains untested. Surprisingly, we find that restricting ribosome biogenesis stimulated human cytomegalovirus (HCMV) replication without suppressing translation. Interfering with ribosomal RNA (rRNA) accumulation triggered nucleolar stress and repressed expression of 1,392 genes, including High Mobility Group Box 2 (HMGB2), a chromatin-associated protein that facilitates cytoplasmic double-stranded (ds) DNA-sensing by cGAS. Furthermore, it reduced cytoplasmic HMGB2 abundance and impaired induction of interferon beta (IFNB1) mRNA, which encodes a critical anti-proliferative, proinflammatory cytokine, in response to HCMV or dsDNA in uninfected cells. This establishes that rRNA accumulation regulates innate immune responses to dsDNA by controlling HMGB2 abundance. Moreover, it reveals that rRNA accumulation and/or nucleolar activity unexpectedly regulate dsDNA-sensing to restrict virus reproduction and regulate inflammation.

Data availability

All sequencing data generated during this study are available from the sequence read archive (SRA) under the BioProject ID PRJNA528082

The following data sets were generated

Article and author information

Author details

  1. Christopher Bianco

    Department of Microbiology, NYU School of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5253-4042
  2. Ian Mohr

    Department of Microbiology, NYU School of Medicine, New York, United States
    For correspondence
    ian.mohr@med.nyu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4921-1998

Funding

National Institute of General Medical Sciences (GM056927)

  • Christopher Bianco
  • Ian Mohr

National Institute of Allergy and Infectious Diseases (AI073898)

  • Ian Mohr

National Institute of Allergy and Infectious Diseases (AI07647)

  • Christopher Bianco

National Institute of Allergy and Infectious Diseases (AI00718)

  • Christopher Bianco

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

Reviewing Editor

  1. Nahum Sonenberg, McGill University, Canada

Version history

  1. Received: June 20, 2019
  2. Accepted: December 16, 2019
  3. Accepted Manuscript published: December 16, 2019 (version 1)
  4. Version of Record published: December 27, 2019 (version 2)

Copyright

© 2019, Bianco & Mohr

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. Christopher Bianco
  2. Ian Mohr
(2019)
Ribosome biogenesis restricts innate immune responses to virus infection and DNA
eLife 8:e49551.
https://doi.org/10.7554/eLife.49551

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https://doi.org/10.7554/eLife.49551

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