2. Academic Validation
  3. Acetylation-Dependent Deubiquitinase OTUD3 Controls MAVS Activation in Innate Antiviral Immunity

Acetylation-Dependent Deubiquitinase OTUD3 Controls MAVS Activation in Innate Antiviral Immunity

  • Mol Cell. 2020 Jul 16;79(2):304-319.e7. doi: 10.1016/j.molcel.2020.06.020.
Zhengkui Zhang 1,  Xiuwu Fang 1,  Xiaojin Wu 2,  Li Ling 1,  Feng Chu 1,  Jingxian Li 3,  Shuai Wang 1,  Jia Zang 3,  Bo Zhang 3,  Sheng Ye 3,  Long Zhang 3,  Bing Yang 4,  Shixian Lin 3,  Huizhe Huang 5,  Aijun Wang 6,  Fangfang Zhou 7
Affiliations

Affiliations

  • 1 Institutes of Biology and Medical Science, Soochow University, Suzhou 215123, China.
  • 2 National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.
  • 3 Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou 310058, China.
  • 4 Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou 310058, China; Department of Pharmaceutical Chemistry and the Cardiovascular Research Institute, University of California, San Francisco, CA 94158, USA.
  • 5 Faculty of Basic Medical Sciences, Chonqing Medical University, Medical College Road 1, 400016 Chongqing, China.
  • 6 Department of Surgery, School of Medicine, University of California, Davis, CA 95817, USA.
  • 7 Institutes of Biology and Medical Science, Soochow University, Suzhou 215123, China. Electronic address: zhoufangfang@suda.edu.cn.
PMID: 32679077 DOI: 10.1016/j.molcel.2020.06.020
Abstract

Accurate regulation of innate immunity is necessary for the host to efficiently respond to invading pathogens and avoid excessive harmful immune pathology. Here we identified OTUD3 as an acetylation-dependent Deubiquitinase that restricts innate Antiviral immune signaling. OTUD3 deficiency in mice results in enhanced innate immunity, a diminished viral load, and morbidity. OTUD3 directly hydrolyzes lysine 63 (Lys63)-linked polyubiquitination of MAVS and thus shuts off innate Antiviral immune response. Notably, the catalytic activity of OTUD3 relies on acetylation of its Lys129 residue. In response to virus Infection, the acetylated Lys129 is removed by SIRT1, which promptly inactivates OTUD3 and thus allows timely induction of innate Antiviral immunity. Importantly, acetyl-OTUD3 levels are inversely correlated with IFN-β expression in influenza patients. These findings establish OTUD3 as a repressor of MAVS and uncover a previously unknown regulatory mechanism by which the catalytic activity of OTUD3 is tightly controlled to ensure timely activation of Antiviral defense.

Keywords

OTUD3; acetylation; deubiquitinase; innate antiviral immunity.

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