The adaptor proteins, STING and MAVS, are components of critical pathogen-sensing pathways that induce innate immunity. Phosphorylation of either adaptor results in activation of the type I interferon pathway. How this phosphorylation is regulated and how it is manipulated by pathogens remain largely unknown. Here, we identified host protein phosphatase, Mg²⁺/Mn²⁺ dependent 1G (PPM1G) as a negative regulator of innate immune pathways and showed that this host system is hijacked by Kaposi’s sarcoma-associated herpesvirus (KSHV). Mechanistically, KSHV tegument protein ORF33 interacts with STING/MAVS and enhances recruitment of PPM1G to dephosphorylate p-STING/p-MAVS for immunosuppression. Inhibition of PPM1G expression improves the antiviral response against both DNA and RNA viruses. Collectively, our study shows that PPM1G restricts both cytosolic DNA– and RNA–sensing pathways to naturally balance the intensity of the antiviral response. Manipulation of PPM1G by KSHV provides an important strategy for immune evasion.

衔接蛋白 STING 和 MAVS 是诱导先天免疫的关键病原体传感途径的组成部分。任一接头的磷酸化导致 I 型干扰素途径的激活。这种磷酸化是如何被调节的，以及它是如何被病原体操纵的，在很大程度上仍然是未知的。在这里，我们鉴定了宿主蛋白磷酸酶 Mg ²⁺ /Mn ²⁺依赖1G（PPM1G）作为先天免疫途径的负调节剂，并表明该宿主系统被卡波西肉瘤相关疱疹病毒（KSHV）劫持。机制上，KSHV 外皮蛋白 ORF33 与 STING/MAVS 相互作用并增强 PPM1G 的募集以使 p-STING/p-MAVS 去磷酸化以进行免疫抑制。PPM1G 表达的抑制提高了对 DNA 和 RNA 病毒的抗病毒反应。总的来说，我们的研究表明 PPM1G 限制了细胞溶质 DNA 和 RNA 传感途径，以自然平衡抗病毒反应的强度。KSHV 对 PPM1G 的操作为免疫逃避提供了重要的策略。