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STING cyclic dinucleotide sensing originated in bacteria
Nature ( IF 64.8 ) Pub Date : 2020-09-02 , DOI: 10.1038/s41586-020-2719-5
Benjamin R Morehouse 1, 2 , Apurva A Govande 1, 2 , Adi Millman 3 , Alexander F A Keszei 4 , Brianna Lowey 1, 2 , Gal Ofir 3 , Sichen Shao 4 , Rotem Sorek 3 , Philip J Kranzusch 1, 2, 5
Affiliation  

Stimulator of interferon genes (STING) is a receptor in human cells that senses foreign cyclic dinucleotides that are released during bacterial infection and in endogenous cyclic GMP–AMP signalling during viral infection and anti-tumour immunity 1 – 5 . STING shares no structural homology with other known signalling proteins 6 – 9 , which has limited attempts at functional analysis and prevented explanation of the origin of cyclic dinucleotide signalling in mammalian innate immunity. Here we reveal functional STING homologues encoded within prokaryotic defence islands, as well as a conserved mechanism of signal activation. Crystal structures of bacterial STING define a minimal homodimeric scaffold that selectively responds to cyclic di-GMP synthesized by a neighbouring cGAS/DncV-like nucleotidyltransferase (CD-NTase) enzyme. Bacterial STING domains couple the recognition of cyclic dinucleotides with the formation of protein filaments to drive oligomerization of TIR effector domains and rapid NAD + cleavage. We reconstruct the evolutionary events that followed the acquisition of STING into metazoan innate immunity, and determine the structure of a full-length TIR–STING fusion from the Pacific oyster Crassostrea 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 signalling and reveal the conservation of a functional cGAS–STING pathway in prokaryotic defence against bacteriophages. Structures of prokaryotic homologues of STING permit the reconstruction of the evolutionary trajectory of its incorporation into metazoan innate immunity, and reveal a role for the conserved cGAS–STING pathway in prokaryotic defence against bacteriophages.

中文翻译:

STING 环状二核苷酸传感起源于细菌

干扰素基因刺激物 (STING) 是人体细胞中的一种受体,可感知在细菌感染期间释放的外来环状二核苷酸以及在病毒感染和抗肿瘤免疫期间释放的内源性环状 GMP-AMP 信号传导 1 – 5 。STING 与其他已知的信号蛋白没有结构同源性 6 – 9,这限制了功能分析的尝试,并阻止了对哺乳动物先天免疫中环状二核苷酸信号传导的起源的解释。在这里,我们揭示了在原核防御岛内编码的功能性 STING 同源物,以及信号激活的保守机制。细菌 STING 的晶体结构定义了一个最小的同源二聚体支架,该支架选择性地响应由邻近的 cGAS/DncV 样核苷酸转移酶 (CD-NTase) 合成的环状 di-GMP。细菌 STING 结构域将环状二核苷酸的识别与蛋白质丝的形成结合起来,以驱动 TIR 效应结构域的寡聚化和快速 NAD + 裂解。我们重建了 STING 获得后生动物先天免疫后的进化事件,并确定了太平洋牡蛎 Crassostrea gigas 的全长 TIR-STING 融合的结构。比较结构分析表明,核心 STING 支架的后生动物特异性添加物如何实现从直接效应器功能到抗病毒转录调控的转变。总之,我们的结果解释了 STING 依赖性信号传导的机制,并揭示了功能性 cGAS-STING 途径在原核生物防御噬菌体中的保守性。
更新日期:2020-09-02
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