title: Pyruvate Carboxylase Activates the RIG-I-like Receptor-Mediated Antiviral Immune Response by Targeting the MAVS signalosome.
abstract: When retinoic acid-inducible gene 1 protein (RIG-I)-like receptors sense viral dsRNA in the cytosol, RIG-I and melanoma differentiation-associated gene 5 (MDA5) are recruited to the mitochondria to interact with mitochondrial antiviral signaling protein (MAVS) and initiate antiviral immune responses. In this study, we demonstrate that the biotin-containing enzyme pyruvate carboxylase (PC) plays an essential role in the virus-triggered activation of nuclear factor kappa B (NF-κB) signaling mediated by MAVS. PC contributes to the enhanced production of type I interferons (IFNs) and pro-inflammatory cytokines, and PC knockdown inhibits the virus-triggered innate immune response. In addition, PC shows extensive antiviral activity against RNA viruses, including influenza A virus (IAV), human enterovirus 71 (EV71), and vesicular stomatitis virus (VSV). Furthermore, PC mediates antiviral action by targeting the MAVS signalosome and induces IFNs and pro-inflammatory cytokines by promoting phosphorylation of NF-κB inhibitor-α (IκBα) and the IκB kinase (IKK) complex, as well as NF-κB nuclear translocation, which leads to activation of interferon-stimulated genes (ISGs), including double-stranded RNA-dependent protein kinase (PKR) and myxovirus resistance protein 1 (Mx1). Our findings suggest that PC is an important player in host antiviral 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: 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: Shengli
authors.initials: S
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Feng
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Xueyuan
authors.initials: X
authors.lastname: Chen
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: 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: 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: Gang
authors.initials: G
authors.lastname: Xu
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: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology*; D000818:Animals; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D000071457:DEAD Box Protein 58 / Q000235:genetics / Q000276:immunology*; D029821:Enterovirus A, Human / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D057809:HEK293 Cells; D022781:Hepatocytes / Q000276:immunology* / Q000821:virology; D006801:Humans; D007113:Immunity, Innate; D053122:Influenza A Virus, H3N2 Subtype / Q000235:genetics / Q000276:immunology*; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology; D000072640:Interferon-Induced Helicase, IFIH1 / Q000235:genetics / Q000276:immunology; D008156:Luciferases / Q000235:genetics / Q000276:immunology; D000072000:NF-KappaB Inhibitor alpha / Q000235:genetics / Q000276:immunology; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D011766:Pyruvate Carboxylase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000276:immunology; D012367:RNA, Viral / Q000235:genetics / Q000276:immunology; D011971:Receptors, Immunologic; D015398:Signal Transduction; D018116:Vesiculovirus / Q000235:genetics / Q000276:immunology*; D019892:eIF-2 Kinase / Q000235:genetics / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D007370:Interferon Type I; C505371:MAVS protein, human; D016328:NF-kappa B; D034741:RNA, Small Interfering; D012367:RNA, Viral; D011971:Receptors, Immunologic; D000072000:NF-KappaB Inhibitor alpha; D008156:Luciferases; C000602769:EIF2AK2 protein, human; D019892:eIF-2 Kinase; C452820:RIGI protein, human; C452815:IFIH1 protein, human; D000071457:DEAD Box Protein 58; D000072640:Interferon-Induced Helicase, IFIH1; D011766:Pyruvate Carboxylase