Tumor Suppressor Rb Selectively Inhibits Innate IFN-β Production And The Underlying Mechanism

Epigenetic regulation of type I interferon (IFN) production in the antiviral innate immune response remains to be fully understood. Several tumor suppressors have been shown to be regulators of immune response and inflammation. Virus infection usually induces stressful response of the host cells with changes of tumor suppressors, and unresolved inflammation contributes to carcinogenesis. However, the non-classical function and underlying mechanisms of tumor suppressors in innate response need further identification. Here we report retinoblastoma protein (Rb), one typical tumor suppressor, was highly expressed in immune organs and upregulated in macrophages by innate signals including TLR ligands and virus infection. Rb deficiency selectively enhanced innate signals-induced production of IFN-P but not IFN-a, TNF, IL-6 in macrophages. RbP1fl/fl Lyz2cre+ Rb-deficient mice were more resistant to lethal virus infection. Rb selectively bound to Ifnb1 enhancer region, but not the promoter of Ifna4, Tnf and 116, by interacting with transcription activator c-Jun, the component of IFN-β enhanceosome. Then Rb recruited histone deacetylases HDAC1 and HDAC8 to attenuate acetylation of H3 and H4 in Ifnb1 promoter, resulting in selective suppression of Ifnb1 transcription. Therefore, Rb selectively inhibits innate IFN-P production by enhancing deacetylation of IFN-β promoter, exhibiting a previous unknown non-classical role in innate immunity.