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

Histone deacetylases (HDACs) play important roles in immunity and inflammation. Through functional screening, we identified HDAC10 as an inhibitor of the type I interferon (IFN) response mediated by interferon regulatory 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 erythematosus (SLE) compared with that in PBMCs from healthy donors. Deficiency in HDAC10 in mouse embryonic 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-independent 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 interaction with LC3-II. Consequently, IRF3 phosphorylation was increased, which resulted in enhanced type I IFN production and antiviral responses. Our findings identify a potential target for improving host defense responses against pathogen infection and for treating autoimmune disease. Description Degradation of HDAC10 during viral infection releases a brake on the induction of the type I interferon response. HDAC10 inhibits antiviral immunity Type I interferons (IFNs) are critical mediators of the antiviral immune response but are also implicated in autoimmune diseases, such as systemic lupus erythematosus (SLE). Zhou et al. found that the abundance of the histone deacetylase HDAC10 was reduced in mouse macrophages in response to various innate immune stimuli. Under unstimulated conditions, HDAC10 interacted with the transcriptional regulator IRF3, preventing its phosphorylation by the kinase TBK1. Upon viral infection, HDAC10 was degraded, enabling IRF3 phosphorylation and activation, as well as induction of the type I IFN response. HDAC10 abundance in immune cells was reduced in patients with SLE compared to healthy controls. These results suggest that HDAC10 may be a potential therapeutic target in the control of viral infections and type I IFN–associated autoimmune diseases.—JFF