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一种E1–E2融合蛋白启动细菌中的抗病毒免疫信号
2023-02-13 11:53

美国科罗拉多大学波尔德分校Aaron T. Whiteley等研究人员合作发现,一种E1–E2融合蛋白启动细菌中的抗病毒免疫信号。该研究于2023年2月8日在线发表于国际一流学术期刊《自然》。

研究人员表示,在所有的生物体中,先天免疫途径感知感染并迅速激活有效的免疫反应,同时避免不适当的激活(自身免疫)。在人类中,先天免疫受体环状GMP-AMP合成酶(cGAS)检测病毒感染,产生核苷酸第二信使环状GMP-AMP(cGAMP),从而启动依赖干STING(stimulator of interferon genes)的抗病毒信号。细菌编码cGAS的演化前身,称为cGAS/DncV样核苷酸转移酶2(CD-NT酶),它检测噬菌体感染并产生各种核苷酸第二信使。细菌CD-NT酶的激活是如何被控制的仍然是未知的。

研究人员表明CD-NTase相关蛋白2(Cap2)通过类似泛素转移酶的机制为细菌CD-NTase的激活提供准备。Cap2-CD-NTase复合物的冷冻电镜结构显示,Cap2是一个一体化的泛素转移酶样蛋白,具有类似于真核E1和E2蛋白的不同结构域。该结构捕捉到一个反应性中间状态,CD-NTase的C端位于Cap2 E1的活性部位,并与AMP结合。Cap2将CD-NTase的C端与一个目标分子结合,使CD-NTase的cGAMP产生增加。研究人员进一步证明,一种特定的内肽酶Cap3通过切割CD-NTase-靶标共轭物来平衡Cap2的活性。这些数据表明,细菌使用一种古老的、最小化的泛素转移酶样系统来控制免疫信号,并提供了对跨生命领域的E1和E2机制的演化见解。

附:英文原文

Title: An E1–E2 fusion protein primes antiviral immune signalling in bacteria

Author: Ledvina, Hannah E., Ye, Qiaozhen, Gu, Yajie, Sullivan, Ashley E., Quan, Yun, Lau, Rebecca K., Zhou, Huilin, Corbett, Kevin D., Whiteley, Aaron T.

Issue&Volume: 2023-02-08

Abstract: In all organisms, innate immune pathways sense infection and rapidly activate potent immune responses while avoiding inappropriate activation (autoimmunity). In humans, the innate immune receptor cyclic GMP–AMP synthase (cGAS) detects viral infection to produce the nucleotide second messenger cyclic GMP–AMP (cGAMP), which initiates stimulator of interferon genes (STING)-dependent antiviral signalling1. Bacteria encode evolutionary predecessors of cGAS called cGAS/DncV-like nucleotidyltransferases2 (CD-NTases), which detect bacteriophage infection and produce diverse nucleotide second messengers3. How bacterial CD-NTase activation is controlled remains unknown. Here we show that CD-NTase-associated protein 2 (Cap2) primes bacterial CD-NTases for activation through a ubiquitin transferase-like mechanism. A cryo-electron microscopy structure of the Cap2–CD-NTase complex reveals Cap2 as an all-in-one ubiquitin transferase-like protein, with distinct domains resembling eukaryotic E1 and E2 proteins. The structure captures a reactive-intermediate state with the CD-NTase C terminus positioned in the Cap2 E1 active site and conjugated to AMP. Cap2 conjugates the CD-NTase C terminus to a target molecule that primes the CD-NTase for increased cGAMP production. We further demonstrate that a specific endopeptidase, Cap3, balances Cap2 activity by cleaving CD-NTase–target conjugates. Our data demonstrate that bacteria control immune signalling using an ancient, minimized ubiquitin transferase-like system and provide insight into the evolution of the E1 and E2 machinery across domains of life.

DOI: 10.1038/s41586-022-05647-4

Source: https://www.nature.com/articles/s41586-022-05647-4

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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