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

Zhengkui Zhang, Xiuwu Fang, Xiaojin Wu, Li Ling, Feng Chu, Jingxian Li, Shuai Wang, Jia Zang, Bo Zhang, Sheng Ye, Long Zhang, Bing Yang, Shixian Lin, Huizhe Huang, Aijun Wang, Fangfang Zhou

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)304-319.e7
JournalMolecular Cell
Volume79
Issue number2
DOIs
StatePublished - Jul 16 2020

Keywords

  • acetylation
  • deubiquitinase
  • innate antiviral immunity
  • OTUD3

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Zhang, Z., Fang, X., Wu, X., Ling, L., Chu, F., Li, J., Wang, S., Zang, J., Zhang, B., Ye, S., Zhang, L., Yang, B., Lin, S., Huang, H., Wang, A., & Zhou, F. (2020). Acetylation-Dependent Deubiquitinase OTUD3 Controls MAVS Activation in Innate Antiviral Immunity. Molecular Cell, 79(2), 304-319.e7. https://doi.org/10.1016/j.molcel.2020.06.020