Glucosidase alpha neutral C promotes influenza virus replication by inhibiting proteosome-dependent degradation of hemagglutinin

The H7N9 influenza virus poses a significant threat to human health, and the mechanism by which it infects humans remains incompletely understood. Our investigation has unveiled significant insights into the role of glucosidase alpha, neutral C (GANC) gene in human H7N9 infections. Through whole genome sequencing (WGS), we identified five low-frequency functional and heterozygous variants of GANC strongly associated with human H7N9 infections compared to healthy controls. Furthermore, we observed a reduction in mRNA and protein expression of GANC following H7N9 virus infection in vitro and in vivo. Subsequent experiments involving GANC demonstrated the promotion of H7N9 virus replication in a stable strain with GANC overexpression. Conversely, GANC knockdown exhibited the ability to restrict influenza A virus (IAV) replication, including H7N9, H9N2, and H1N1, both in vitro and in vivo. This inhibition was mediated by GANC's ability to promote the degradation of H7N9 hemagglutinin (HA). Moreover, we discovered that GANC knockdown facilitated the degradation of HA in a proteasome-dependent manner. The inhibition caused by GANC knockdown was mediated by promoting direct binding of HA with the proteasome 26S subunit, non-ATPase, 1 (PSMD1) and PSMD2. All five variants in the GANC gene reduced their ability to promote H7N9 virus replication, and also diminished the levels of GANC-induced HA protein expression. Our findings revealed a novel mechanism by which GANC inhibits the proteasome-dependent degradation of HA to promote H7N9 virus replication. These results suggest that GANC may play an important role in IAV replication.