title: MAVS regulates apoptotic cell death by decreasing K48-linked ubiquitination of voltage-dependent anion channel 1.
abstract: The mitochondrial antiviral signaling protein MAVS (IPS-1, VISA, or Cardif) plays an important role in the host defense against viral infection by inducing type I interferon. Recent reports have shown that MAVS is also critical for virus-induced apoptosis. However, the mechanism of MAVS-mediated apoptosis induction remains unclear. Here, we show that MAVS binds to voltage-dependent anion channel 1 (VDAC1) and induces apoptosis by caspase-3 activation, which is independent of its role in innate immunity. MAVS modulates VDAC1 protein stability by decreasing its degradative K48-linked ubiquitination. In addition, MAVS knockout mouse embryonic fibroblasts (MEFs) display reduced VDAC1 expression with a consequent reduction of the vesicular stomatitis virus (VSV)-induced apoptosis response. Notably, the upregulation of VDAC1 triggered by VSV infection is completely abolished in MAVS knockout MEFs. We thus identify VDAC1 as a target of MAVS and describe a novel mechanism of MAVS control of virus-induced apoptotic cell death.
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Guan
authors.forename: Zirui
authors.initials: Z
authors.lastname: Zheng
authors.forename: Ting
authors.initials: T
authors.lastname: Song
authors.forename: Xiang
authors.initials: X
authors.lastname: He
authors.forename: Changzhi
authors.initials: C
authors.lastname: Xu
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Shengli
authors.initials: S
authors.lastname: Ma
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Quanbin
authors.initials: Q
authors.lastname: Xu
authors.forename: Ye
authors.initials: Y
authors.lastname: Cao
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Yang
authors.forename: Xiaoxing
authors.initials: X
authors.lastname: Ge
authors.forename: Congwen
authors.initials: C
authors.lastname: Wei
authors.forename: Hui
authors.initials: H
authors.lastname: Zhong
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism*; D002460:Cell Line; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000821:virology; D054884:Host-Pathogen Interactions; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060066:Protein Interaction Maps; D055503:Protein Multimerization; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D054875:Ubiquitination; D015854:Up-Regulation; D054243:Vesicular Stomatitis / Q000821:virology; D018116:Vesiculovirus / Q000502:physiology; D050995:Voltage-Dependent Anion Channel 1 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D053148:Caspase 3; D050995:Voltage-Dependent Anion Channel 1; C512612:MAVS protein, mouse