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

Molecular Cell
Zhengkui ZhangFangfang Zhou

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.

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Citations

Oct 22, 2020·Biomolecules·George VereAdan Pinto-Fernandez
Jan 20, 2021·Cellular & Molecular Immunology·Koji OnomotoMitsutoshi Yoneyama
Mar 21, 2021·Open Heart·James J DiNicolantonioJorge Barroso-Aranda
May 22, 2021·Trends in Microbiology·Dirk SchlüterMichael Naumann
Jun 30, 2021·The Journal of Immunology : Official Journal of the American Association of Immunologists·Ziwen ZhouWuhan Xiao
Aug 16, 2021·The Journal of Biological Chemistry·Nathan A Snyder, Gustavo M Silva
Oct 30, 2021·Advanced Biology·Petra Neumann-StaubitzHeinz Neumann
Oct 17, 2021·The Journal of Immunology : Official Journal of the American Association of Immunologists·Junji ZhuWuhan Xiao
Sep 3, 2021·The Journal of Clinical Investigation·Wilian Correa-MacedoErwin Schurr

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