PPM1G restricts innate immune signaling mediated by STING and MAVS and is hijacked by KSHV for immune evasion.
PPM1G restricts innate immune signaling mediated by STING and MAVS and is hijacked by KSHV for immune evasion.
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PPM1G 限制 STING 和 MAVS 介导的先天免疫信号，并被 KSHV 劫持以进行免疫逃避
DOI：
10.1126/sciadv.abd0276
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发表时间：
2020-11
期刊：
影响因子：
13.6
通讯作者：
Deng H
中科院分区：
文献类型：
--
作者：
Yu K;Tian H;Deng H
一种保守的疱疹病毒被膜蛋白募集宿主蛋白磷酸酶PPM 1G到MAVS和MASTING以进行免疫逃避。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分。任一衔接子的磷酸化导致I型干扰素途径的激活。这种磷酸化是如何调节的，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，我们确定了宿主蛋白磷酸酶，Mg 2 +/Mn 2+依赖性1G（PPM 1G）作为先天免疫途径的负调节因子，并表明该宿主系统被卡波西肉瘤相关疱疹病毒（KSHV）劫持。在机制上，KSHV皮层蛋白ORF 33与STING/MAVS相互作用，并增强PPM 1G的募集以使p-STING/p-MAVS去磷酸化用于免疫抑制。PPM 1G表达的抑制提高了对DNA和RNA病毒的抗病毒应答。总的来说，我们的研究表明，PPM 1G限制了胞质DNA和RNA传感途径，以自然平衡抗病毒反应的强度。通过KSHV操纵PPM 1G提供了免疫逃避的重要策略。
A conserved herpesvirus tegument protein recruits host protein phosphatase PPM1G to inactivate STING and MAVS for immune evasion. 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.
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影响因子：
16
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