ID: 105: Activation of type I and III interferon response by mitochondrial and peroxisomal MAVS and inhibition by hepatitis C virus

Sensing viruses by pattern recognition receptors (PRR) triggers the innate immune system of the host cell and activates immune signaling cascades like the RIG-I/IRF3 pathway. Mitochondrial antiviral-signaling protein (MAVS) is the crucial adaptor protein of this pathway localized on mitochondria, peroxisomes and mitochondria associated membranes (MAMs). Activation of MAVS leads to the production of type I and type III interferon (IFN) as well as interferon stimulated genes (ISGs). To refine the role of MAVS subcellular localization for the induction of type I and III IFN responses in hepatocytes, we generated cell lines with organelle-targeted MAVS and characterized innate immune response after viral infection. We established various functional and genetic knock-out cell systems reconstituted to express exclusively mitochondrial or peroxisomal MAVS. Infection with diverse RNA viruses mounted comparable levels of type I and III IFN expression irrespective of MAVS subcellular localization. To determine whether viral counteraction of MAVS is affected in these systems we employed infection of cells with the hepatitis C virus (HCV), a major causative agent of chronic liver diseases with a high propensity to establish persistence. This virus efficiently cleaves MAVS via a viral protease residing in nonstructural protein 3 (NS3). We found that both mitochondrial and peroxisomal MAVS were efficiently cleaved by NS3 and this cleavage was required to suppress activation of the IFN response. Taken together, our findings indicate comparable activation of the IFN response by peroxisomal and mitochondrial MAVS in hepatocytes and efficient counteraction of both MAVS species by the HCV NS3 protease.