title: MAVS Promotes Inflammasome Activation by Targeting ASC for K63-Linked Ubiquitination via the E3 Ligase TRAF3.
abstract: Stringent control of inflammasome signaling pathway is important for maintaining immunological balance, yet the molecular mechanisms responsible for its tight regulation are still poorly understood. In this study, we found that the signaling pathway dependent on mitochondrial antiviral signaling protein (MAVS) was required for the optimal activation of apoptosis-associated specklike protein (ASC)-dependent inflammasome. In particular, TNFR-associated factor 3 was found to be a direct E3 ligase for ASC. Ubiquitination of ASC at Lys(174) was critical for speck formation and inflammasome activation. Deficiency in MAVS or TNFR-associated factor 3 impaired ASC ubiquitination and cytosolic aggregates formation, resulting in reduced inflammasome response upon RNA virus infection. This study has identified a previously unrecognized role of MAVS in the regulation of inflammasome signaling and provided molecular insight into the mechanisms by which ubiquitination of ASC controls inflammasome activity through the formation of ASC specks.
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing 100850, People's Republic of China;
authors.forename: Kai
authors.initials: K
authors.lastname: Guan
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing 100850, People's Republic of China;
authors.forename: Congwen
authors.initials: C
authors.lastname: Wei
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing 100850, People's Republic of China;
authors.forename: Zirui
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing 100850, People's Republic of China;
authors.forename: Ting
authors.initials: T
authors.lastname: Song
authors.affiliation: Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, People's Republic of China; and.
authors.forename: Feixiang
authors.initials: F
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing 100850, People's Republic of China;
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing 100850, People's Republic of China;
authors.forename: Ye
authors.initials: Y
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing 100850, People's Republic of China;
authors.forename: Shengli
authors.initials: S
authors.lastname: Ma
authors.affiliation: Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, People's Republic of China; and.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing 100850, People's Republic of China;
authors.forename: Quanbin
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Life Sciences, Peking University, Beijing 100871, People's Republic of China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Xia
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Life Sciences, Peking University, Beijing 100871, People's Republic of China gj@pku.edu.cn hexiang_spring@163.com towall@yahoo.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Gu
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing 100850, People's Republic of China; gj@pku.edu.cn hexiang_spring@163.com towall@yahoo.com.
authors.forename: Xiang
authors.initials: X
authors.lastname: He
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing 100850, People's Republic of China; gj@pku.edu.cn hexiang_spring@163.com towall@yahoo.com.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhong
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000276:immunology* / Q000378:metabolism; D053468:CARD Signaling Adaptor Proteins; D015151:Immunoblotting; D047468:Immunoprecipitation; D058847:Inflammasomes / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D034622:RNA Interference; D015398:Signal Transduction / Q000276:immunology*; D048008:TNF Receptor-Associated Factor 3 / Q000276:immunology*; D054875:Ubiquitination; D014777:Virus Diseases / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D058847:Inflammasomes; D048008:TNF Receptor-Associated Factor 3; C512612:MAVS protein, mouse; C498534:Pycard protein, mouse