A Combined Proteomics/Genomics Approach Links Hepatitis C Virus Infection with Nonsense-Mediated mRNA Decay

Hepatitis C virus (HCV) is a leading cause of liver disease, but insight into virus-host interactions remains limited. We systematically used affinity purification/mass spectrometry to define the host interactions of all ten HCV proteins in hepatoma cells. We combined these studies with RNAi knockdown of corresponding genes using a two-step scoring approach to generate a map of 139 high-confidence HCV-host protein-protein interactions. We found mitochondrial proteins highly involved in HCV infection and characterized an interaction between the viral core protein and host protein within bgcn homolog (WIBG). Expression of core prevents WIBG from binding its regular interaction partners Y14 and Magoh, two known mediators of the nonsense-mediated mRNA decay pathway. We discovered that this surveillance pathway is disrupted in HCV-infected cells, causing potentially harmful transcripts to accumulate. Our study provides a comprehensive view of HCV-host interactions and uncovers mechanisms for how HCV perturbs host functions during infection. [Display omitted] •Combined AP-MS and RNAi approaches identify key HCV-human protein interactions•Mitochondrial proteins interact with viral proteins core, p7, and NS4B•VAP proteins bind the NS4A cofactor within the NS3/4A protease•HCV infection disrupts the nonsense-mediated mRNA decay pathway Ramage et al. report a hepatitis C virus (HCV)-host protein-protein interactome that identifies host factors and pathways implicated in HCV pathogenesis. They show that HCV blocks nonsense-mediated mRNA surveillance, a potential host restriction pathway, in infected hepatoma cells.