Porcine deltacoronavirus NS7a antagonizes JAK/STAT pathway by inhibiting the interferon-stimulated gene factor 3 (ISGF3) formation

The accessory proteins of coronaviruses play a crucial role in facilitating virus-host interactions and modulating host immune responses. Previous study demonstrated that the NS7a protein of porcine deltacoronavirus (PDCoV) partially hindered the host immune response by impeding the induction of IFN-alpha/beta. However, the potential additional functions of NS7a protein in evading innate immunity have yet to be elucidated. This study aimed to investigate the mechanism of PDCoV NS7a protein regulating the JAK/STAT signaling pathway. We presented evidence that NS7a effectively inhibited ISRE promoter activity and ISGs transcription. NS7a hindered STAT1 phosphorylation, interacted with STAT2 and IRF9, and further impeded the formation and nuclear accumulation of ISGF3. Furthermore, comparative analysis of NS7a across different PDCoV strains revealed that the mutation of Leu4 to Pro4 led to an increase in the molecular weights of NS7a and disrupted its inhibition on the JAK/STAT signaling pathway. This finding implied that NS7a with key amino acids may be an indicator of virulence for PDCoV strains. Taken together, this study revealed a novel role of NS7a in antagonizing the IFN-I signaling pathway.