2. Academic Validation
  3. Degradation of HDAC10 by autophagy promotes IRF3-mediated antiviral innate immune responses

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

  • Sci Signal. 2022 Dec 20;15(765):eabo4356. doi: 10.1126/scisignal.abo4356.
Wenkai Zhou 1 2 3,  Jiaming Wang 1,  Xin Wang 1,  Bingjing Wang 1,  Zhehui Zhao 4,  Jie Fu 4,  Yan Wang 4,  Xuan Zhang 5,  Ping Zhu 2 3,  Minghong Jiang 1,  Xuetao Cao 1
Affiliations

Affiliations

  • 1 Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China.
  • 2 Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510100, China.
  • 3 Guangdong Provincial Key Laboratory of Pathogenesis, Targeted Prevention and Treatment of Heart Disease, Guangzhou, Guangdong 510080, China.
  • 4 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100050, China.
  • 5 Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China.
PMID: 36538592 DOI: 10.1126/scisignal.abo4356
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.

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