Pyruvate Carboxylase Activates The RIG-I-like Receptor-Mediated Antiviral Immune Response By Targeting The MAVS Signalosome

Pyruvate carboxylase (PC), which locates on mitochondria, is a biotin-containing enzyme. PC catalyzes pyruvate transfer to oxaloacetate and is HCO3--and MgATP-dependent. PC distributes in many eukaryotes and prokaryotes. This reaction that PC catalyzes the carboxylation of pyruvate, is a pivotal role in providing intermediary for many biochemistry metabolism. Therefore, PC participates in numerous biological processes, including glyceroneogenesis in adipose tissue, and glutamate production in astrocytes. The reaction catalysed by PC have been studied extensively and detailed, however, its role in innate immunity response has never been established. We found that overexpression of PC strong increased the virus-induction IFNs and pro-inflammatory cytokines expression.Thus PC is a positive regulator of virus-triggered IFNs and pro-inflammatory cytokines, which has the function of against viral replication. Then we performed the antiviral experiments to assess the function of PC in this action. And our res?lts showed that PC represses the RNA virus replication, including IAV, VSV, and EV71. While, we generated a PC-specific knockdown stable cell line (PC-KD) to detect whether the endogenous PC is required for the antiviral action. And we show that depletion of PC promoting the viral replication. To further confirm the increased viral replication is responsive for PC, we restore the expression of PC in PC-KD cells, and miraculously, the increased viral replication is repressed. These res?lts demonstrate that PC plays a significantly role in antiviral reaction.When RIG-I-like receptors sense viral dsRNA in the cytosol, RIG-I and MDA5 are recruited to the mitochondria to interact with mitochondrial antiviral signaling protein (MAVS) and initiate antiviral immune responses. PC is located on mitochondria and represses the RNA viral replication, including IAV, VSV and EV71 which potent activate the RLR signaling pathway. Co-immunoprecipitation experiments indicate that PC is interacted with MAVS and MAVS-associated components. And we show that PC can translocate from mitochondria matrix to cytoplasm by infected with SeV (MOI=1). The further experiments demonstrate that PC promotes the phosphorylation of I?B? and IKK complex, as well as NF-?B nuclear translocation, which leads to activation of interferon-stim?lated genes (ISGs), including PKR and Mxl. Our findings suggest that PC is an important player in host antiviral signaling.