Figure 4

TLR3-dependent and RIG-I-dependent signaling to the innate immune response: specific cleavage of signaling adapters by HCV NS3–4A protease. Engagement of endosome-associated TLR3 by dsRNA recruits the TRIF adaptor, resulting in the activation of TBK-1 and IKKɛ kinases that phosphorylate IRF-3 and IRF-7. TRIF also signals NF-κB activation via the IKKα/β complex, which phosphorylates IκBα, resulting in the release of the NF-κB DNA-binding subunits. The RIG-1 pathway activates NF-κB and IRF-3/7, following the recognition of incoming viral ribonucleoprotein complexes. RIG-I, through C-terminal RNA helicase domain, interacts with viral dsRNA and through the CARD domains interacts with the MAVS/IPS/VISA/Cardif adaptor. MAVS contains a transmembrane domain (TM) that localizes this adaptor to the mitochondria. NS3–4A protease activity of HCV cleaves the C-terminal domain of MAVS at Cys-508, disrupts RIG-I signaling to IFN activation and establishes persistent infection. NS3–4A also targets the TRIF adaptor molecule in the TLR3-dependent pathway (modified from Hiscott et al., 2006).