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

Zhongying Cao,Shi Liu,Shengli Zhu,Gang Xu,Yaqin Zhou,Nanfang Peng,Ying Zhu,Jian Feng,Xueyuan Chen,Xiaodan Yang

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.

Highlights

The innate immune response is a critical host defense system against microbial pathogen invasion
We demonstrate that Pyruvate carboxylase (PC) represses the replication of RNA viruses such as influenza A virus (IAV), vesicular stomatitis virus (VSV), and human enterovirus 71 (EV71) by targeting the mitochondrial antiviral signaling protein (MAVS) signalosome to activate NF-κ B signaling
Viral RNA binding drives retinoic acid-inducible gene protein (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) to undergo conformational changes that facilitate their recruitment to the mitochondria to interact with the adaptor molecule MAVS, which recruits E3 ligases TRAF3, TRAF6, and other adaptors to form the MAVS signalosome and introduce the production of type I IFNs and pro-inflammatory cytokines[12,13]

Summary

Introduction

The innate immune response is a critical host defense system against microbial pathogen invasion. TLRs are type I transmembrane proteins with ectodomains containing leucine-rich repeats, which mediate the recognition of pathogen-associated molecular patterns; a transmembrane region; and cytosolic Toll-interleukin-1 receptor (TIR) domains that activate downstream signaling pathways[4,5]. Viral RNA binding enables the N-terminal-CARDs of RLRs to interact with the adaptor molecule MAVS (alternatively known as IPS-1/CARDIF/VISA), a mitochondrial outer membrane protein composed of a N-terminal single CARD, a central proline-rich region that contains two tumor necrosis factor receptor-associated factor (TRAF) binding motifs and a transmembrane domain (TM)[3,11,12,13,14]. Pyruvate carboxylase (PC) is a member of biotin-containing enzyme family that catalyzes the ATP-dependent carboxylation of pyruvate to oxaloacetate[25] This is a very important anaplerotic reaction for various pivotal biochemical pathways in the central metabolism.

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Conclusion