STING Polymer Structure Reveals Mechanisms for Activation, Hyperactivation, and Inhibition
STING Polymer Structure Reveals Mechanisms for Activation, Hyperactivation, and Inhibition
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DOI：
10.1101/552166
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发表时间：
2019-02
期刊：
影响因子：
64.5
通讯作者：
S. L. Ergun;D. Fernández;T. Weiss;Lingyin Li
中科院分区：
文献类型：
--
作者：
S. L. Ergun;D. Fernández;T. Weiss;Lingyin Li
中枢先天免疫蛋白STING如何被其配体激活仍不清楚。在这里，使用结构生物学和生物化学，我们报告了后生动物第二信使2 '3'-cGAMP诱导人STING同源二聚体的闭合和STING C末端尾部的释放，这暴露了STING二聚体上的聚合界面，并导致通过半胱氨酸残基148形成二硫键连接的聚合物。致病性高活性STING突变位于C148侧翼并依赖于二硫键形成，或位于C末端尾结合位点并引起组成性C末端尾释放和聚合。最后，细菌环状-二-GMP诱导替代的活性STING构象，以协同方式激活STING，并充当2 '3'-cGAMP信号传导的部分拮抗剂。我们的见解解释了STING信号的严格控制，给出了不同的背景激活信号，并为自身免疫综合征治疗提供了一种新的治疗假设。
How the central innate immune protein, STING, is activated by its ligands remains unknown. Here, using structural biology and biochemistry, we report that the metazoan second messenger 2’3’-cGAMP induces closing of the human STING homodimer and release of the STING C-terminal tail, which exposes a polymerization interface on the STING dimer and leads to the formation of disulfide-linked polymers via cysteine residue 148. Disease-causing hyperactive STING mutations either flank C148 and depend on disulfide formation or reside in the C-terminal tail binding site and cause constitutive C-terminal tail release and polymerization. Finally, bacterial cyclic-di-GMP induces an alternative active STING conformation, activates STING in a cooperative manner, and acts as a partial antagonist of 2’3’-cGAMP signaling. Our insights explain the tight control of STING signaling given varying background activation signals and provide a novel therapeutic hypothesis for autoimmune syndrome treatment.