title: Methylcrotonoyl-CoA carboxylase 1 potentiates RLR-induced NF-κB signaling by targeting MAVS complex.
abstract: RNA virus infections are detected by the RIG-I family of receptors, which signal through the adaptor molecule mitochondrial antiviral signaling (MAVS). MAVS then recruits the adaptor's tumor necrosis factor receptor-associated factor (TRAF) 3 and TRAF6, which in turn activate IRF3 and NF-κB, respectively, to induce interferons (IFNs) and inflammatory responses. Here we show that the biotin-containing enzyme methylcrotonoyl-CoA carboxylase 1 (MCCC1) enhances virus-induced, MAVS-mediated IFN and inflammatory cytokine expression through the NF-κB signaling pathway. MCCC1 knockdown strongly inhibits induction of IFNs and inflammatory cytokines. Furthermore, MCCC1 shows extensive antiviral activity toward RNA viruses, including influenza A virus, human enterovirus 71, and vesicular stomatitis virus. Here, we have elucidated the mechanism underlying MCCC1-mediated inhibition of viral replication. MCCC1 interacts with MAVS and components of the MAVS signalosome and contributes to enhanced production of type I IFNs and pro-inflammatory cytokines by promoting phosphorylation of the IκB kinase (IKK) complex and NF-κB inhibitor-α (IκBα), as well as NF-κB nuclear translocation. This process leads to activation of IFNs and cytokine expression and subsequent activation of IFN-stimulated genes, including double-stranded RNA-dependent protein kinase PKR and myxovirus resistance protein 1. These findings demonstrate that MCCC1 plays an essential role in virus-triggered, MAVS-mediated activation of NF-κB signaling.
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Zhongying
authors.initials: Z
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Zhangchuan
authors.initials: Z
authors.lastname: Xia
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Yaqin
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Xiaodan
authors.initials: X
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Hao
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Nanfang
authors.initials: N
authors.lastname: Peng
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Shi
authors.initials: S
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhu
mesh_terms: D000072283:A549 Cells; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000998:Antiviral Agents / Q000378:metabolism; D019735:Carbon-Carbon Ligases / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D000071457:DEAD Box Protein 58 / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007370:Interferon Type I / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000998:Antiviral Agents; D016207:Cytokines; D018836:Inflammation Mediators; D007370:Interferon Type I; C505371:MAVS protein, human; D016328:NF-kappa B; D034741:RNA, Small Interfering; D048029:TNF Receptor-Associated Factor 6; D000072000:NF-KappaB Inhibitor alpha; D000071457:DEAD Box Protein 58; D019735:Carbon-Carbon Ligases; C021573:methylcrotonoyl-CoA carboxylase