GRP78 exerts antiviral function against influenza A virus infection by activating the IFN/JAK-STAT signaling

Influenza is an acute viral respiratory infection that causes mild to severe illness in humans and animals. Current studies show that glucose-regulated protein 78 (GRP78) can exert crucial functions during viral infection; however, the mechanism by which GRP78 regulates influenza A virus (IAV) infection remains unclear. In the present study, we found that IAV infection increased GRP78 expression. Overexpression of GRP78 significantly inhibited IAV replication, as indicated by reduced viral mRNA levels, protein levels, and viral titers. Mechanistically, Type I interferon (IFN) response signaling is upregulated during IAV infection by GRP78. Further study showed that GRP78 interacts with tyrosine kinase 2 (TYK2) and enhances its phosphorylation, thereby activating downstream STAT1/2 and antiviral IFN-stimulated gene (ISG) expression. Collectively, these results demonstrate an important mechanism by which GRP78 exerts in innate antiviral effect in IAV infection. This mechanism could be used as a therapeutic target for anti-influenza treatment.