HACE1 Negatively Regulates Virus-Triggered Type I IFN Signaling by Impeding the Formation of the MAVS-TRAF3 Complex
He-Ting Mao,
Yan Wang,
Juan Cai,
Jun-Ling Meng,
Yu Zhou,
Yu Pan,
Xiao-Ping Qian,
Yu Zhang,
Jun Zhang
Affiliations
He-Ting Mao
Key Laboratory of Medical Immunology (National Health and Family Planning Commission of China), Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
Yan Wang
Key Laboratory of Medical Immunology (National Health and Family Planning Commission of China), Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
Juan Cai
Key Laboratory of Medical Immunology (National Health and Family Planning Commission of China), Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
Jun-Ling Meng
Key Laboratory of Medical Immunology (National Health and Family Planning Commission of China), Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
Yu Zhou
Key Laboratory of Medical Immunology (National Health and Family Planning Commission of China), Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
Yu Pan
Key Laboratory of Medical Immunology (National Health and Family Planning Commission of China), Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
Xiao-Ping Qian
Key Laboratory of Medical Immunology (National Health and Family Planning Commission of China), Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
Yu Zhang
Key Laboratory of Medical Immunology (National Health and Family Planning Commission of China), Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
Jun Zhang
Key Laboratory of Medical Immunology (National Health and Family Planning Commission of China), Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
During virus infection, the cascade signaling pathway that leads to the production of proinflammatory cytokines is controlled at multiple levels to avoid detrimental overreaction. HACE1 has been characterized as an important tumor suppressor. Here, we identified HACE1 as an important negative regulator of virus-triggered type I IFN signaling. Overexpression of HACE1 inhibited Sendai virus- or poly (I:C)-induced signaling and resulted in reduced IFNB1 production and enhanced virus replication. Knockdown of HACE1 expression exhibited the opposite effects. Ubiquitin E3 ligase activity of the dead mutant HACE1/C876A had a comparable inhibitory function as WT HACE1, suggesting that the suppressive function of HACE1 on virus-induced signaling is independent of its E3 ligase activity. Further study indicated that HACE1 acted downstream of MAVS and upstream of TBK1. Mechanistic studies showed that HACE1 exerts its inhibitory role on virus-induced signaling by disrupting the MAVS-TRAF3 complex. Therefore, we uncovered a novel function of HACE1 in innate immunity regulation.
