Mpox virus poxin-schlafen fusion protein suppresses innate antiviral response by sequestering STAT2

Mpox virus (MPXV) has to establish efficient interferon (IFN) antagonism for effective replication. MPXV-encoded IFN antagonists have not been fully elucidated. In this study, the IFN antagonism of poxin-schlafen (PoxS) fusion gene of MPXV was characterized. MPXV PoxS was capable of decreasing cGAS-produced 2'3'-cGAMP, like its ortholog poxin of vaccinia virus, which is the first known cytosolic nuclease that hydrolyses the 3'-5' bond of 2'3'-cyclic GMP-AMP (cGAMP). However, MPXV PoxS did not suppress cGAS-STING-mediated type I IFN production. Instead, MPXV PoxS antagonized basal and type I IFN-induced expression of IFN-stimulated genes such as OAS1, SAMD9, SAMD9L, ISG15, ISG56 and IFIT3. Consistently, MPXV PoxS inhibited both basal and type I IFN-stimulated activity of interferon-stimulated response elements, but did not affect activation of IFN-γ-activated sites. Mechanistically, MPXV PoxS interacted with STAT2 and sequestered it in the cytoplasm. Both the viral schlafen fusion and the active site of 2'3'-cGAMP nuclease were required for STAT2 sequestration and consequent suppression of IFN-stimulated gene expression. MPXV PoxS conferred resistance to the suppression of MPXV replication by type I IFN. Taken together, our findings suggested that MPXV PoxS counteracts host antiviral response by sequestering STAT2 to circumvent basal and type I IFN-induced expression of antiviral genes.