Publication from Fangfang ZHOU lab, Molecular Cell


In July 2020, Professor Zhou Fangfang's research group published a research paper entitled " Acetylation-Dependent Deubiquitinase OTUD3 Controls MAVS Activation in Innate Antiviral Immunity " in the Molecular Cell.


In viral infection, the host quickly produces high levels of IFN-Is and proinflammatory cytokines to clean virus through pattern-recognition receptor (PRR)-initiated innate immunity. As insufficient interferon production results in chronic infection whereas excessive interferon results in autoimmune and/or inflammatory disease, innate immunity must be tightly regulated to efficiently respond to invading pathogen and meanwhile avoid excessive harmful immune pathology. This raises the question how host cells limit innate immune signals to extremely low levels and meanwhile ensure its timely activation to deal with the challenge of pathogens?


In this study, we found the quiescence and activation of innate immunity are mechanistically interrelated and precisely switched by mechanism that requires an acetylation-dependent deubiquitinase OTUD3. Firstly, we systematically performed a DUB activity-based screening in which we found the OTUD3 was severely inactivated by infection with virus. OTUD3 deficiency in mice results in enhanced innate immunity, a diminished viral load, and morbidity. OTUD3 directly hydrolyzes K63-linked poly-ubiquitination of MAVS and thus shuts off innate antiviral immune response. Notably, the catalytic activity of OTUD3 relies on acetylation of its lysine129 residue. In response to virus infection, the acetylated lysine129 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.


We have revealed an unknown interplay and correlation between DUB activity control and antiviral innate immunity of the host, in which OTUD3 is the first acetylation-dependent DUB identified. This regulation of OTUD3 prevents innate antiviral immunity from unwanted auto- or extra-activation and meanwhile enables the efficient immune response against virus. These mechanistic studies not only deepened our understanding of the mechanisms underlying antiviral defense of the host but also provided a window to effectively intervene in antiviral immunity.


Zhang Zhengkui, Fang Xiuwu and Xiaojin Wu are the first authors of this paper. In addition, Wang Shuai, Chu Feng, Ling Li, et al. participated in the research. This work is supported by the Ministry of Science and Technology of China (2016YFA0502500), National Natural Science Foundation of China (82041009, 31571460,31900650, 31671457, 91753139 and 31925013), the National Natural Science Foundation of Jiangsu Province(BK20180043), the China Postdoctoral Science Foundation (2018M640522, BX2018020), the Social Development Plan of Jiangsu Province (BE2018651) and the Research and Practice Innovation Program for Universities and Graduate Students in Jiangsu Province (KYCX17_2036).