Pyruvate Carboxylase Activates the RIG-I-like Receptor-Mediated Antiviral Immune Response by Targeting the MAVS signalosome

Sci Rep. 2016 Feb 24;6:22002. doi: 10.1038/srep22002.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / immunology*
  • Animals
  • Cell Line, Tumor
  • Cytokines / genetics
  • Cytokines / immunology
  • DEAD Box Protein 58 / genetics
  • DEAD Box Protein 58 / immunology*
  • Enterovirus A, Human / genetics
  • Enterovirus A, Human / immunology*
  • Gene Expression Regulation
  • Genes, Reporter
  • HEK293 Cells
  • Hepatocytes / immunology*
  • Hepatocytes / virology
  • Humans
  • Immunity, Innate
  • Influenza A Virus, H3N2 Subtype / genetics
  • Influenza A Virus, H3N2 Subtype / immunology*
  • Interferon Type I / genetics
  • Interferon Type I / immunology
  • Interferon-Induced Helicase, IFIH1 / genetics
  • Interferon-Induced Helicase, IFIH1 / immunology
  • Luciferases / genetics
  • Luciferases / immunology
  • NF-KappaB Inhibitor alpha / genetics
  • NF-KappaB Inhibitor alpha / immunology
  • NF-kappa B / genetics
  • NF-kappa B / immunology
  • Pyruvate Carboxylase / antagonists & inhibitors
  • Pyruvate Carboxylase / genetics
  • Pyruvate Carboxylase / immunology*
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / immunology
  • RNA, Viral / genetics
  • RNA, Viral / immunology
  • Signal Transduction
  • Vesiculovirus / genetics
  • Vesiculovirus / immunology*
  • eIF-2 Kinase / genetics
  • eIF-2 Kinase / immunology

Substances

  • Adaptor Proteins, Signal Transducing
  • Cytokines
  • Interferon Type I
  • MAVS protein, human
  • NF-kappa B
  • RNA, Small Interfering
  • RNA, Viral
  • NF-KappaB Inhibitor alpha
  • Luciferases
  • EIF2AK2 protein, human
  • eIF-2 Kinase
  • DDX58 protein, human
  • IFIH1 protein, human
  • DEAD Box Protein 58
  • Interferon-Induced Helicase, IFIH1
  • Pyruvate Carboxylase