Abstract
Sensing viruses by pattern recognition receptors (PRR) triggers the innate immune system of the host cell and activates immune signaling cascades such as the RIG-I/IRF3 pathway. Mitochondrial antiviral-signaling protein (MAVS, also known as IPS-1, Cardif, and VISA) is the crucial adaptor protein of this pathway localized on mitochondria, peroxisomes and mitochondria-associated membranes of the endoplasmic reticulum. Activation of MAVS leads to the production of type I and type III interferons (IFN) as well as IFN stimulated genes (ISGs). To refine the role of MAVS subcellular localization for the induction of type I and III IFN responses in hepatocytes and its counteraction by the hepatitis C virus (HCV), we generated various functional and genetic knock-out cell systems that were reconstituted to express mitochondrial (mito) or peroxisomal (pex) MAVS, exclusively. Upon infection with diverse RNA viruses we found that cells exclusively expressing pexMAVS mounted sustained expression of type I and III IFNs to levels comparable to cells exclusively expressing mitoMAVS. To determine whether viral counteraction of MAVS is affected by its subcellular localization we employed infection of cells with HCV, a major causative agent of chronic liver disease with a high propensity to establish persistence. This virus efficiently cleaves MAVS via a viral protease residing in its nonstructural protein 3 (NS3) and this strategy is thought to contribute to the high persistence of this virus. We found that both mito- and pexMAVS 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 pex- and mitoMAVS in hepatocytes and efficient counteraction of both MAVS species by the HCV NS3 protease.
Highlights
Vertebrates developed several defense mechanisms against invading pathogens
We found that the hepatitis C virus (HCV) protease residing in nonstructural protein 3 (NS3) efficiently cleaves MAVS independent from its subcellular localization
Our results indicate a largely localization-independent activation of the IFN response by MAVS in hepatocytes and its efficient counteraction by the HCV NS3 protease
Summary
Vertebrates developed several defense mechanisms against invading pathogens. Upon viral infection foreign RNA or DNA is introduced into the host cell where it is detected by highly conserved pattern recognition receptors (PRRs) sensing distinct non-self motifs [1,2,3,4,5,6,7]. Well known examples of PRRs are RIG-I (Retinoic acid-Induced Gene I) and MDA5 (Melanoma Differentiation-Associated protein 5) that both are cytosolic RNA helicases recognizing primarily 5’-triphosphorylated and long Upon interaction with RNA, both RIG-I-like receptors (RLR) induce a signaling cascade which leads to the production of type I and III Interferon (IFN) as well as IFN stimulated genes (ISGs). Activation of MAVS induces a prion-like oligomerization of the protein, forming large signaling platforms [14]. These platforms lead to the activation of NFκB and IFN regulatory factor 3 and 7 (IRF3, IRF7), which upon nuclear translocation drive the expression of IFNs and other cytokine genes [9,10,11,12, 15]. In principle the same pathway is utilized upon activation of MDA5 [14, 16, 17]
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