Diacylglycerol acyltransferase 1 (DGAT1) Functions as a Cellular “Hub” to Target Hepatitis C Virus Proteins NS5A and Core to Lipid Droplets

Abstract

The association of Hepatitits C Virus (HCV) proteins core and NS5A to lipid droplets plays an essential role in the HCV life cycle. Triglycerides stored in lipid droplets can be generated by two diacylglycerol acyltransferase enzymes, DGAT1 or DGAT2. We have previously shown that DGAT1 is critical for the recruitment of the HCV core protein to lipid droplets and thereby regulates viral assembly. This recruitment inhibits lipolysis of core‐coated droplets stabilizing these droplets as intracellular assembly platforms for HCV infection and potentially contributing to HCV‐induced steatosis. We screened all HCV proteins for interactions with DGAT1 and identified NS5A as a novel DGAT1 interaction partner. DGAT1, and not DGAT2, forms a trimolecular complex with core and NS5A and stabilizes the otherwise weak cellular interaction between the two viral proteins. Trafficking of NS5A to lipid droplets is dependent on active DGAT1 as shown in knockdown studies or after treatment with a specific DGAT1 inhibitor. Our data underscore the central role of DGAT1 as a host factor for HCV infection and identify DGAT1 as a novel link between core and NS5A proteins in cells. We propose that the newly identified interactions of DGAT1 with NS5A and core serve to guide trafficking of both viral proteins to the same subset of lipid droplets –those generated by DGAT1 ‐ where viral assembly can take place.