STING cyclic dinucleotide sensing originated in bacteria.
STING cyclic dinucleotide sensing originated in bacteria.
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DOI：
10.1038/s41586-020-2719-5
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发表时间：
2020-10
期刊：
影响因子：
64.8
通讯作者：
Kranzusch PJ
中科院分区：
文献类型：
--
作者：
Morehouse BR;Govande AA;Millman A;Keszei AFA;Lowey B;Ofir G;Shao S;Sorek R;Kranzusch PJ
干扰素基因刺激因子（STING）是人类细胞中的一种受体，其感测细菌感染期间释放的外源环状二核苷酸以及病毒感染和抗肿瘤免疫期间的内源性环状GMP-AMP信号传导。STING与其他已知的信号传导蛋白没有结构同源性，限制了功能分析并阻止了对哺乳动物先天免疫中环状二核苷酸信号传导起源的解释。在这里，我们发现了原核防御岛内编码的功能性STING同源物，并揭示了信号激活的保守机制。细菌STING的晶体结构定义了最小的同源二聚体支架，其选择性地响应于由邻近的cGAS/DncV样核苷酸转移酶（CD-NT酶）合成的c-di-GMP。细菌STING结构域将环状二核苷酸识别与蛋白丝形成偶联以驱动TIR效应子结构域寡聚化和快速NAD+切割。我们重建了获得STING后的进化事件进入后生动物先天免疫，并确定了来自太平洋牡蛎C的全长TIR-STING融合体的结构。千兆。比较结构分析证明了多细胞动物特异性添加到核心STING支架如何实现从直接效应子功能到调节抗病毒转录的切换。总之，我们的研究结果解释了STING依赖性信号传导的机制，并揭示了原核噬菌体防御中功能性cGAS-STING途径的保守性。
Stimulator of interferon genes (STING) is a receptor in human cells that senses foreign cyclic dinucleotides released during bacterial infection and endogenous cyclic GMP–AMP signaling during viral infection and antitumor immunity. STING shares no structural homology with other known signaling proteins, limiting functional analysis and preventing explanation for the origin of cyclic dinucleotide signaling in mammalian innate immunity. Here we discover functional STING homologues encoded within prokaryotic defense islands and reveal a conserved mechanism of signal activation. Crystal structures of bacterial STING define a minimal homodimeric scaffold that selectively responds to c-di-GMP synthesized by a neighboring cGAS/DncV-like nucleotidyltransferase (CD-NTase) enzyme. Bacterial STING domains couple cyclic dinucleotide recognition with protein filament formation to drive TIR effector domain oligomerization and rapid NAD+ cleavage. We reconstruct the evolutionary events following acquisition of STING into metazoan innate immunity and determine the structure of a full-length TIR-STING fusion from the Pacific oyster C. gigas. Comparative structural analysis demonstrates how metazoan-specific additions to the core STING scaffold enabled a switch from direct effector function to regulation of antiviral transcription. Together, our results explain the mechanism of STING-dependent signaling and reveal conservation of a functional cGAS-STING pathway in prokaryotic bacteriophage defense.
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