Mpox virus D8L protein binds to STAT1 and inhibits its phosphorylation to antagonize IFN-induced signaling.

In August 2024, mpox was declared a public health emergency. However, little is known about how the proteins of the mpox virus (MPXV) interact with host innate immunity. This study identified that the D8L protein of MPXV inhibited the interferon (IFN)-mediated antiviral innate immune response and suppressed the mRNA transcription and protein expression of several IFN-stimulated genes, including Cig5, MX2, ISG56, IFITM1, OAS1, and ISG15. Mechanistically, D8L prevented antiviral immune responses by interacting with signal transducer and activator of transcription 1 (STAT1). Furthermore, D8L interacted with the SH2 structural domain of the STAT1 protein but not with other regions. The point-mutant plasmids capable of binding STAT1 were D8L-9-11, D8L-13, and D8L-18. In addition, D8L attenuated IFN responses by inhibiting the phosphorylation and nuclear translocation of STAT1. These findings provide valuable information for the development of novel antiviral therapies.