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 hydrolyzes 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.

猴痘病毒（MPXV）需建立高效的干扰素（IFN）拮抗作用以实现有效复制。MPXV编码的IFN拮抗剂尚未完全阐明。本研究对MPXV的poxin-schlafen（PoxS）融合基因的IFN拮抗作用进行了表征。MPXV PoxS能够降低cGAS产生的2′3′-cGAMP，其同源物牛痘病毒poxin是首个被发现的胞质核酸酶，可水解2′3′-环鸟苷酸腺苷酸（cGAMP）的3′-5′键。然而，MPXV PoxS并未抑制cGAS-STING介导的I型IFN产生。相反，MPXV PoxS拮抗基础状态及I型IFN诱导的IFN刺激基因（如OAS1、SAMD9、SAMD9L、ISG15、ISG56和IFIT3）的表达。一致地，MPXV PoxS抑制基础状态及I型IFN刺激的干扰素刺激反应元件活性，但不影响IFN-γ激活位点的活化。机制上，MPXV PoxS与STAT2相互作用并将其隔离在细胞质中。病毒schlafen融合结构域及2′3′-cGAMP核酸酶的活性位点均是STAT2隔离及后续IFN刺激基因表达抑制所必需的。MPXV PoxS赋予MPXV对I型IFN抑制其复制的抗性。综上，我们的研究结果表明，MPXV PoxS通过隔离STAT2来规避基础状态及I型IFN诱导的抗病毒基因表达，从而拮抗宿主抗病毒反应。