Nuclear RPSA senses viral nucleic acids to promote the innate inflammatory response.

Innate sensors initiate the production of type I interferons (IFN-I) and proinflammatory cytokines to protect host from viral infection. Several innate nuclear sensors that mainly induce IFN-I production have been identified. Whether there exist innate nuclear sensors that mainly induce proinflammatory cytokine production remains to be determined. By functional screening, we identify 40 S ribosomal protein SA (RPSA) as a nuclear protein that recognizes viral nucleic acids and predominantly promotes proinflammatory cytokine gene expression in antiviral innate immunity. Myeloid-specific Rpsa-deficient mice exhibit less innate inflammatory response against infection with Herpes simplex virus-1 (HSV-1) and Influenza A virus (IAV), the viruses replicating in nucleus. Mechanistically, nucleus-localized RPSA is phosphorylated at Tyr204 upon infection, then recruits ISWI complex catalytic subunit SMARCA5 to increase chromatin accessibility of NF-κB to target gene promotors without affecting innate signaling. Our results add mechanistic insights to an intra-nuclear way of initiating proinflammatory cytokine expression in antiviral innate defense.