DHAV-1 3C protein promotes viral proliferation by antagonizing type I interferon via upregulating the ANXA2 protein

The picornavirus 3C protein plays a crucial role in viral infection. One of its functions is inhibiting the immune response by cleaving or degrading innate immune-related proteins to promote viral infection. Annexin A2 (ANXA2) is a multifunctional host protein that plays a key role in various cellular processes, it also participates in viral infection. However, whether the ANXA2 protein interacts with the picornavirus 3C protein to regulate viral infection and its effect on type I interferon (IFN) has not been reported. In this study, we found that the 3C protein of duck hepatitis A virus 1 (DHAV-1) interacts with the ANXA2 protein and upregulates ANXA2 expression. Moreover, the ANXA2 protein interacts with the cGAS, STING, RIG-I, MDA5, MAVS, and TBK1 proteins, suppresses its activated IFN-β and ISRE promoter activity, promotes RIG-I, MDA5, and TBK1 protein degradation through caspase-dependent pathway, thereby inhibiting IFN-β production and promoting DHAV-1 proliferation. This study lays a theoretical foundation for further understanding the interaction between viruses and hosts, as well as for analyzing the function of the picornavirus 3C protein and the ANXA2 protein. It also suggests a novel pathway, such as targeting key sites on the 3C protein to upregulate ANXA2, for a target-based antiviral strategy.