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STING环状二核苷酸感知能力起源于细菌

时间:2020-09-05 13:11来源:葡京娱乐赌城 作者:葡京捕鱼 点击:
本期文章:《自然》:Online/在线发表 美国丹娜法伯癌症研究所Philip J. Kranzusch小组发现,STING环状二核苷酸感知能力起源于细菌。2020年9月2日,《自然》杂志在线发表了这项成果。 研

本期文章:《自然》:Online/在线发表

美国丹娜法伯癌症研究所Philip J. Kranzusch小组发现,STING环状二核苷酸感知能力起源于细菌。2020年9月2日,《自然》杂志在线发表了这项成果。

研究人员发现了在原核生物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的晶体结构定义了一个最小的同源二聚体支架,其选择性响应由邻近cGAS/DncV样核苷酸转移酶(CD-NTase)酶合成的c-di-GMP。细菌的STING结构域将环状二核苷酸识别与蛋白丝形成结合起来,从而驱动TIR效应子结构域寡聚化和NAD+快速剪切。

 

研究人员重建了STING获得在后生动物先天免疫力中的进化事件,并确定了来自太平洋牡蛎Crassostrea gigas的全长TIR-STING融合体的结构。比较结构分析表明,向核心STING支架添加后生动物特异性成分如何使从直接效应子功能转变为抗病毒转录的调控。

 

因此,这些结果解释了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。

 

据悉,STING(stimulator of interferon genes)是人类细胞中的一种受体,可感知细菌感染过程中释放的外来环状二核苷酸以及病毒感染和抗肿瘤免疫中的内源性环状GMP-AMP信号。STING与其他已知的信号蛋白没有结构同源性,从而限制了功能分析并无法解释哺乳动物先天免疫中环状二核苷酸信号的起源。

 

附:英文原文

Title: STING cyclic dinucleotide sensing originated in bacteria

Author: Benjamin R. Morehouse, Apurva A. Govande, Adi Millman, Alexander F. A. Keszei, Brianna Lowey, Gal Ofir, Sichen Shao, Rotem Sorek, Philip J. Kranzusch

Issue&Volume: 2020-09-02

Abstract: 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 signalling during viral infection and antitumour immunity1–5. STING shares no structural homology with other known signalling proteins6–9, limiting functional analysis and preventing explanation of the origin of cyclic dinucleotide signalling in mammalian innate immunity. Here we discover functional STING homologues encoded within prokaryotic defence 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 neighbouring 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 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 conservation of a functional cGAS-STING pathway in prokaryotic bacteriophage defence.

DOI: 10.1038/s41586-020-2719-5

Source: https://www.nature.com/articles/s41586-020-2719-5

期刊信息

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
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