PPM1A regulates antiviral signaling by antagonizing TBK1-mediated STING phosphorylation and aggregation.
PPM1A regulates antiviral signaling by antagonizing TBK1-mediated STING phosphorylation and aggregation.
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PPM1A 通过拮抗 TBK1 介导的 STING 磷酸化和聚集来调节抗病毒信号传导
DOI：
10.1371/journal.ppat.1004783
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发表时间：
2015-03
期刊：
影响因子：
6.7
通讯作者：
Sun Q
中科院分区：
文献类型：
--
作者：
Li Z;Liu G;Sun L;Teng Y;Guo X;Jia J;Sha J;Yang X;Chen D;Sun Q
干扰素基因的刺激剂（也称为Mita和Eris）对于保护宿主的侵袭至关重要。以其磷酸酶活性依赖性方式的刺痛，并与此刺激，ppm1a催化脱磷酸化和tbk1在体外。我们提供的证据表明，tbk1以磷酸化依赖性方式促进了刺激性的聚集，而PPM1A通过去磷酸化和TBK1的方式来拮抗刺激性的聚集刺激和TBK1相互调节以实现有效的抗病毒信号激活，并且ppm1a脱磷酸化和TBK1，从而平衡了这种抗病毒信号转导。
天生的抗病毒免疫对于迅速检测并消除了刺激性的宿主防御系统，内质网（ER）相关的蛋白质在响应于DNA病毒感染的I型激活中起着重要的作用刺伤可能会引起致命的炎症性疾病，因此必须精确控制刺激活性，以确保适当的抗病毒信号转化在这项研究中，我们发现PPM1A与STING的物理相互作用，并且对刺激介导的抗病毒信号的机理相互作用。此外，它们的去磷酸化。依赖活性的方式，PPM1A通过去磷酸化和TBK1抑制刺激性，我们的研究不仅揭示了STING和TBK1与彼此相互调节以引起抗病毒信号，而且还表明PPM1A拮抗了靶向刺激的刺激聚集。 TBK1，从而保持适当的抗病毒反应。
Stimulator of interferon genes (STING, also known as MITA and ERIS) is critical in protecting the host against DNA pathogen invasion. However, the molecular mechanism underlying the regulation of STING remains unclear. Here, we show that PPM1A negatively regulates antiviral signaling by targeting STING in its phosphatase activity-dependent manner, and in a line with this, PPM1A catalytically dephosphorylates STING and TBK1 in vitro. Importantly, we provide evidence that whereas TBK1 promotes STING aggregation in a phosphorylation-dependent manner, PPM1A antagonizes STING aggregation by dephosphorylating both STING and TBK1, emphasizing that phosphorylation is crucial for the efficient activation of STING. Our findings demonstrate a novel regulatory circuit in which STING and TBK1 reciprocally regulate each other to enable efficient antiviral signaling activation, and PPM1A dephosphorylates STING and TBK1, thereby balancing this antiviral signal transduction. Innate antiviral immunity is essential for the host defense system that rapidly detects and eliminates invading viruses. STING, an endoplasmic reticulum (ER)-associated protein, plays important roles in the activation of type I IFN in response to DNA virus infection. Whereas excessive activation of STING can potentially cause lethal inflammatory diseases, STING activity must thus be precisely controlled to ensure the proper antiviral signaling transduction. However, the mechanisms of how STING activation is regulated are not fully understood. In this study, we find that PPM1A physically interacts with STING and negatively regulates STING-mediated antiviral signaling. Mechanistically, we find that PPM1A functions as a phosphatase that targets both STING and TBK1 for their dephosphorylation. Moreover, our study demonstrates that while TBK1 enhances STING aggregation in a kinase activity-dependent manner, PPM1A suppresses STING aggregation by dephosphorylating both STING and TBK1. Collectively, our study not only reveals that STING and TBK1 reciprocally regulate each other’s activity to elicit antiviral signaling, but also shows that PPM1A antagonizes STING aggregation by targeting both STING and TBK1, thereby maintaining proper antiviral responses.
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影响因子：
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作者：
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影响因子：
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作者：
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