STING Activation by Translocation from the ER Is Associated with Infection and Autoinflammatory Disease.
STING Activation by Translocation from the ER Is Associated with Infection and Autoinflammatory Disease.
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DOI：
10.1016/j.chom.2015.07.001
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发表时间：
2015-08-12
影响因子：
30.3
通讯作者：
Yan N
中科院分区：
文献类型：
--
作者：
Dobbs N;Burnaevskiy N;Chen D;Gonugunta VK;Alto NM;Yan N
STING是一种ER相关的膜蛋白，对于病原体的先天免疫传感至关重要。STING介导的通过TBK 1/IRF 3信号传导轴的IFN-I途径的活化涉及环状二核苷酸结合及其从ER到囊泡的易位。然而，这些事件是如何协调的，以及STING激活的确切机制仍然知之甚少。在这里，我们发现志贺氏菌效应蛋白IpaJ通过阻断STING信号从ER到ERGIC的易位来有效抑制STING信号传导，即使在二核苷酸结合的情况下也是如此。使用纯化的组分重建揭示STING易位作为最大信号转导的限速事件。此外，发现与人类自身免疫相关的STING突变引起组成型ER退出，并独立于cGAMP结合激活STING。总之，这些数据为STING调控的ER保留和ERGIC/高尔基体运输机制提供了令人信服的证据，该机制被细菌病原体破坏，并在人类遗传疾病中解除调控。
STING is an ER-associated membrane protein that is critical for innate-immune sensing of pathogens. STING-mediated activation of the IFN-I pathway through the TBK1/IRF3 signaling axis involves both cyclic-dinucleotide binding, and its translocation from the ER to vesicles. However, how these events are coordinated, and the exact mechanism of STING activation, remain poorly understood. Here, we found that the Shigella effector protein IpaJ potently inhibits STING signaling by blocking its translocation from the ER to ERGIC, even in the context of dinucleotide binding. Reconstitution using purified components revealed STING translocation as the rate-limiting event in maximal signal transduction. Furthermore, STING mutations associated with autoimmunity in humans were found to cause constitutive ER exit, and to activate STING independent of cGAMP binding. Together, these data provide compelling evidence for an ER-retention and ERGIC/Golgi-trafficking mechanism of STING regulation that is subverted by bacterial pathogens and is deregulated in human genetic disease.