Ribosome biogenesis restricts innate immune responses to virus infection and DNA
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
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Impact of TIFIA and UBF depletion on genome wide responses to dsDNASRA BioProject, PRJNA528082.
Article and author information
Author details
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.
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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