['Hepatitis C virus (HCV) is a major human viral pathogen that causes chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. In most cases, acute HCV infection becomes persistent, at least in part due to viral evasion of host innate immune response. Although HCV genomic RNA contains pathogen-associated molecular pattern (PAMP) that is able to induce host interferon responses, HCV can shut down the responses by using the viral NS3/4A protease to cleave MAVS/VISA and TRIF, two key adaptor molecules essential for the interferon signaling activation. The aim of this study was to explore a novel NS3/4A-independent mechanism HCV utilizes to evade host innate immune responses.', 'We used the interferon promoter-reporter system to screen HCV encoded proteins for their activities to suppress the interferon signaling and to determine the molecular targets of viral proteins. Co-immunoprecipitation, confocal microscopy, and siRNA-based gene silencing were used to investigate the molecular mechanism.', 'We found that, in addition to NS3/4A, NS4B can suppress double-stranded RNA or RNA virus induced interferon activation. NS4B interacts with STING/MITA, an important molecule that mediates the HCV PAMP induced interferon signaling. Mechanistic studies indicated that NS4B disrupts the interactions between STING/MITA and TBK1.'] Does hepatitis C virus NS4B block the interaction of STING and TBK1 to evade host innate immunity?