Degradation of HDAC10 by autophagy promotes IRF3-mediated antiviral innate immune responses

Histone deacetylases (HDACs) play important roles in immunity and inflammation. Through functional screen-ing, we identified HDAC10 as an inhibitor of the type I interferon (IFN) response mediated by interferon regu-latory factor 3 (IRF3). HDAC10 abundance was decreased in mouse macrophages in response to innate immune stimuli and was reduced in peripheral blood mononuclear cells (PBMCs) from patients with systemic lupus er-ythematosus (SLE) compared with that in PBMCs from healthy donors. Deficiency in HDAC10 in mouse embry-onic fibroblasts and in mice promoted the expression of genes encoding type I IFNs and of IFN-stimulated genes (ISGs), leading to enhanced antiviral responses in vitro and in vivo. HDAC10 bound in a deacetylase-indepen-dent manner to IRF3 in uninfected cells to inhibit the phosphorylation of IRF3 at Ser396 by TANK-binding kinase 1 (TBK1). Upon viral infection, HDAC10 was targeted for autophagy-mediated degradation through its interac-tion with LC3-II. Consequently, IRF3 phosphorylation was increased, which resulted in enhanced type I IFN pro-duction and antiviral responses. Our findings identify a potential target for improving host defense responses against pathogen infection and for treating autoimmune disease.