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

Citations Over TimeTop 10% of 2022 papers

Abstract

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.

Related Papers

• → Vaccinia Virus Protein C6 Is a Virulence Factor that Binds TBK-1 Adaptor Proteins and Inhibits Activation of IRF3 and IRF7(2011)171 cited
• → African swine fever virus MGF360-11L negatively regulates cGAS-STING-mediated inhibition of type I interferon production(2022)89 cited
• → Zebrafish NDRG1a Negatively Regulates IFN Induction by Promoting the Degradation of IRF7(2018)23 cited
• → Ctenopharyngodon idella TBK1 activates innate immune response via IRF7(2018)23 cited
• → Interferon-β (IFNB; IFN-β); interferon-α/β receptor 1 (IFNAR1); TANK-binding kinase 1 (TBK1); interferon regulatory factor 3 (IRF3); IRF7(2011)