title: HACE1 Negatively Regulates Virus-Triggered Type I IFN Signaling by Impeding the Formation of the MAVS-TRAF3 Complex.
abstract: 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.
authors.affiliation: 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. maoheting@126.com.
authors.forename: He-Ting
authors.initials: HT
authors.lastname: Mao
authors.affiliation: 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. wangyan_tcell@hotmail.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 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. caijuan1919@163.com.
authors.forename: Juan
authors.initials: J
authors.lastname: Cai
authors.affiliation: 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. mengjunling46@sina.com.
authors.forename: Jun-Ling
authors.initials: JL
authors.lastname: Meng
authors.affiliation: 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. germany163@sina.com.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: 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. panyuzhaoning@163.com.
authors.forename: Yu
authors.initials: Y
authors.lastname: Pan
authors.affiliation: 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. qianxp1959@163.com.
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Qian
authors.affiliation: 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. zhangyu007@bjmu.edu.cn.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: 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. junzhang@bjmu.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D016899:Interferon-beta / Q000037:antagonists & inhibitors*; D011070:Poly I-C; D011119:Polynucleotides / Q000276:immunology; D055503:Protein Multimerization; D029082:Sendai virus / Q000276:immunology*; D015398:Signal Transduction; D048008:TNF Receptor-Associated Factor 3 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D014779:Virus Replication
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C505371:MAVS protein, human; D011119:Polynucleotides; D048008:TNF Receptor-Associated Factor 3; C090656:TRAF3 protein, human; D016899:Interferon-beta; C497506:HACE1 protein, human; D044767:Ubiquitin-Protein Ligases; D011070:Poly I-C
keywords: HACE1; MAVS; TRAF3; inflammation; interferon