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 1392 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. (145 words).
Highlights
The minting of ribosomes, the molecular machines that synthesize polypeptides, is subject to stringent controls that coordinate demand for ribosomes with intracellular processes and environmental cues, including nutritional status and responses to physiological stress (Iadevaia et al, 2014)
While the 47S precursor-ribosomal RNA (rRNA) is transcribed by RNA Polymerase I (RNAPI) within the nucleolus, 5S rRNA is generated by RNA Polymerase III (RNAPIII) and mRNAs encoding ribosomal proteins are produced by RNA Polymerase II (RNAPII) in the nucleoplasm
Given the universal dependence of virus protein synthesis upon cellular ribosomes, it is assumed that ribosome biogenesis would support ongoing protein synthesis and virus reproduction
Summary
The minting of ribosomes, the molecular machines that synthesize polypeptides, is subject to stringent controls that coordinate demand for ribosomes with intracellular processes and environmental cues, including nutritional status and responses to physiological stress (Iadevaia et al, 2014). It is among the most energetically demanding processes in the cell and requires all three eukaryotic RNA polymerases. Ribosomes play critical roles in infection biology where polypeptide synthesis by obligate intracellular parasites such as viruses is absolutely reliant upon cellular ribosomes (Mohr and Sonenberg, 2012; Stern-Ginossar et al, 2019).
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