STING在宿主天然免疫信号通路中的调节作用

STING(stimulator of interferon genes)是天然免疫信号通路中一种新发现的蛋白质,在防御病毒及胞内细菌感染、介导Ⅰ型IFN产生过程中发挥重要功能.来自病原体的B型DNA与5′-3p dsRNA暴露在宿主细胞中后被相应的模式识别受体识别,通过不同的通路传递信号给STING.STING随后通过相似的机制招募TBK1激活IRF3,诱导干扰素表达.对细菌中的环二核苷酸c-di-GMP和c-di-AMP,STING则可以直接作为模式识别受体引发Ⅰ型干扰素反应.此外STING还能激活STAT6诱导特异趋化因子产生,吸引各种免疫细胞抵抗病毒感染.本文通过对STING的发现、结构、定位、功能、机理以及调节机制进行综述,以期为揭示病毒逃逸天然免疫调节机制和抗病毒新型免疫调节剂提供新的思路.     

新型胞质DNA感受通路：cGAS-STING的研究进展

细胞胞质中存在的游离DNA一直被宿主的固有免疫系统当做潜在的危险信号,但免疫系统识别和清除这些危险信号的机制还不明确.近几年有研究发现,DNA感受器(DNA sensor)是宿主感受DNA和免疫防御的桥梁,目前已经有超过10种DNA感受器被发现,而干扰素刺激基因(stimulator of interferon genes,STING,也称为TMEM173、MPYS、MITA和ERIS)作为一种DNA感受通路下游关键的接头分子,在感受胞质DNA和免疫防御方面起着重要的信号传递作用,胞质中的DNA可通过DNA感受器激活STING,再激活Ⅰ型干扰素和其他细胞因子,进而启动机体的免疫反应.近些年,胞质中游离DNA如何激活STING,进而如何在体内启动免疫反应以产生抗病毒或抗菌作用的机制研究取得了显著进展.最近,在哺乳动物细胞中发现了一种新型的核酸转移酶cGAS(cyclic GMP-AMPsynthase),它能识别DNA并能产生一种内源性的环化二核苷酸cGAMP(cyclic GMP-AMP)激活STING.本文将最近关于cGAS的发现、胞质DNA通过cGAS激活STING及STING活化后激活机体免疫反应的机制进行了综述.     

cGAS-STING信号通路在心血管疾病中的作用

环鸟苷酸腺苷酸合成酶(cyclic GMP-AMP synthase,cGAS)作为一种DNA感受器通过识别胞质DNA产生环鸟苷酸-腺苷酸(cyclic GMP-AMP,cGAMP)并激活干扰素基因刺激因子(stimulator of interferon gene,STING)及一系列下游通路从而介导免疫及炎症反应....     

STING信号通路的研究进展

干扰素基因刺激因子(Stimulator of interferon gene,STING)作为固有免疫系统的关键性接头蛋白,在外源或内源DNA介导的免疫应答中发挥重要作用,广泛参与宿主体内的多种信号传导过程。概述了STING信号通路分子机制及其在抗病毒感染、自身免疫疾病、神经系统疾病和肿瘤中的作用,介绍了常见的STING激动剂和抑制剂,以期为STING的进一步研究提供参考。     

cGAS-STING通路在细菌感染中的作用

环磷酸鸟苷-腺苷合成酶(cyclic guanosine monophosphate-adenosine monophosphate synthase,c GAS,又称为MB21D1或C6orf150)是一种胞质DNA感受器,能识别胞质中的双链DNA(double strand DNA,ds DNA),并形成2∶2型复合物,催化腺苷三磷酸(adenosine triphosphate,ATP)和鸟苷三磷酸(guanosine triphosphate,GTP)形成环鸟苷酸腺苷酸(cyclic guanosine monophosphate-adenosine monophosphate,c GAMP)。c GAMP作为第二信使激活干扰素基因刺激分子(stimulator of interferon gene,STING),进而产生Ⅰ型干扰素及其他细胞因子。近年来,多项研究表明,c GAS-STING通路在病毒感染免疫中发挥重要作用,包括人类免疫缺陷病毒(human immunodeficiency virus,HIV)、人乳头瘤病毒(human papilloma virus,HPV)和乙型肝炎病毒(hepatitis B virus,HBV)等,但关于c GAS在细菌感染中的作用的研究较少。就近年来国内外对c GAS及c GAS在细菌感染中的作用作一综述,为其在细菌感染相关的应用研究提供思路和借鉴。     

cGAS/STING信号通路参与猪圆环病毒2型诱导猪肺泡巨噬细胞产生Ⅰ型干扰素

为研究猪圆环病毒2型 (Porcine circovirus type 2,PCV2) 感染的猪肺泡巨噬细胞 (Porcine alveolar macrophages,PAMs) 分泌Ⅰ型干扰素信号通路,以PCV2病毒感染PAMs为研究对象,采用酶联免疫吸附测定 (Enzyme-linked immunosorbent assay,ELISA)、实时荧光定量PCR和Western blotting,分析PCV2感染对PAMsⅠ型干扰素的诱导、cGAS/STING信号通路相关基因mRNA和蛋白表达的影响,并应用靶向cGAS和STING特异性siRNA、抑制剂BX795和BAY 11-7082,解析cGAS、STING、TBK1和NF-κB/P65在PAMs生成Ⅰ型干扰素中的作用。结果显示,PAMs感染PCV2病毒48 h后Ⅰ型干扰素的表达量显著升高 (P＜0.05),cGAS mRNA的表达量在感染48 h和72 h后显著升高 (P＜0.01),STING mRNA表达量在PCV2感染72 h后显著上升 (P＜0.01),TBK1 mRNA、IRF3 mRNA感染48 h后显著升高 (P＜0.01)。PCV2能够显著升高PAMs胞浆STING、TBK1和IRF3蛋白含量,降低胞浆NF-κB/p65的含量,促进NF-κB/p65和IRF3入核。敲低PAMs中cGAS或STING表达水平后,PCV2感染PAMs 48 h后,Ⅰ型干扰素的表达水平显著下降 (P＜0.01);BAX795抑制TBK1后,PCV2感染PAMs 48 hⅠ型干扰素的表达水平显著下降 (P＜0.01),BAY 11-7082 抑制NF-κB/P65表达后,PCV2感染PAMs 48 h I型干扰素的表达量与PCV2组相比无显著性差异 (P＞0.05)。结果表明,PAMs感染PCV2后通过cGAS/STING/TBK1/IRF3信号通路诱导Ⅰ型干扰素分泌。     

TLR4信号通路介导病毒性急性肺损伤与ARDS的研究进展

Toll样受体(Toll-like receptors,TLR)是参与非特异性免疫的Ⅰ型跨膜蛋白分子,可识别病原相关分子模式(Pathogen-associated molecular patterns,PAMP)并在病原体侵入体内的早期阶段激活机体的免疫应答,在响应宿主细胞对微生物病原体的识别中起重要作用,是机体抵抗感染疾病的重要屏障.以流感病毒和冠状病毒为代表的呼吸道病毒感染在临床具有极高的发病率和死亡率.此类病毒感染细胞后可通过模式识别受体和病原体相关分子模式相互作用激活宿主的先天免疫系统,诱发宿主产生过激的炎症反应从而引发"细胞因子风暴",最终导致急性肺损伤与急性呼吸窘迫综合症而致人死亡.因此,本文就Toll样受体家族中的Toll样受体4介导的信号通路为对象,就其介导的信号通路在流感病毒与冠状病毒复制及其在导致病毒性急性肺损伤与ARDS形成中的作用及靶向抑制该通路治疗病毒性肺炎的研究进展作一综述,以供同行参考.     

非洲猪瘟病毒I226R蛋白抑制cGAS-STING通路介导的天然免疫应答

本研究旨在探究非洲猪瘟病毒(African swine fever virus, ASFV) I226R蛋白(I226R protein, pI226R)抑制cGAS-STING信号通路的作用机制。利用双荧光素酶报告系统和实时荧光定量PCR (real-time quantitative PCR, qPCR)证明pI226R显著抑制cGAS-STING通路介导的I型干扰素及干扰素刺激相关基因的产生。免疫共沉淀及激光共聚焦显微镜试验发现pI226R与cGAS蛋白相互作用。免疫印迹分析证明pI226R通过自噬-溶酶体途径促进cGAS蛋白的降解。同时,pI226R阻碍了cGAS与E3泛素连接酶三基序蛋白56 (tripartite motif protein 56, TRIM56)的结合,导致cGAS的单泛素化减弱,从而抑制了cGAS的活化和cGAS-STING通路的激活。总之,本研究证明ASFV pI226R通过拮抗cGAS进而抑制宿主的抗病毒天然免疫反应,进一步增加了对研究ASFV免疫逃逸机制的理解,为疫苗的研发提供了理论基础。     

本期重点推介

正昆虫先天免疫主要依赖于模式识别受体(pattern recognition receptor,PRRs)通过识别入侵微生物表面的保守分子来区分异己。肽聚糖识别蛋白(peptidoglycan recognition protein,PGRP)是这类识别受体之一。抗菌肽是昆虫体液免疫中的重要组分,具有杀死病原体的作用。病原微生物侵染还可引发机体大量合成过氧化氢(H2O2)等活性氧分子。为探究家蝇Musca domestica肽聚糖识别蛋白PGRP-SC在应对     

宿主识别与应答胞质内DNA入侵的信号转导机制

固有免疫是宿主防御病原微生物入侵的第一道防线。宿主通过胚系基因编码的模式识别受体(pathogen recognition receptor,PRR)监测微生物的病原相关分子模式(病毒核酸等),迅速启动免疫应答反应。宿主自身的核酸如果错误地出现在细胞质中,也会被模式识别受体识别,引发自身免疫疾病。STING(stimulator of interferon genes)是最近鉴定出的内质网接头蛋白,可以动态监控细胞内DNA以及环二核苷酸(cyclic dinucleotides,CDNs)的异常存在,发挥承上启下的抗微生物感染的枢纽功能。该文概述STING介导的细胞信号通路前沿进展,并对有待突破的科学问题作出展望。     

Curcuminoids as inhibitors of thioredoxin reductase: A receptor based pharmacophore study with distance mapping of the active site

Curcumin is the yellow pigment of turmeric that interacts irreversibly forming an adduct with thioredoxin reductase (TrxR), an enzyme responsible for redox control of cell and defence against oxidative stress. Docking at both the active sites of TrxR was performed to compare the potency of three naturally occurring curcuminoids, namely curcumin, demethoxy curcumin and bis-demethoxy curcumin. Results show that active sites of TrxR occur at the junction of E and F chains. Volume and area of both cavities is predicted. It has been concluded by distance mapping of the most active conformations that Se atom of catalytic residue SeCYS498, is at a distance of 3.56 from C13 of demethoxy curcumin at the E chain active site, whereas C13 carbon atom forms adduct with Se atom of SeCys 498. We report that at least one methoxy group in curcuminoids is necessary for interation with catalytic residues of thioredoxin. Pharmacophore of both active sites of the TrxR receptor for curcumin and demethoxy curcumin molecules has been drawn and proposed for design and synthesis of most probable potent antiproliferative synthetic drugs.     

A Unique Protease Cleavage Site Predicted in the Spike Protein of the Novel Pneumonia Coronavirus (2019-nCoV) Potentially Related to Viral Transmissibility

正Dear Editor,In December 2019, a novel human coronavirus caused an epidemic of severe pneumonia(Coronavirus Disease 2019,COVID-19) in Wuhan, Hubei, China(Wu et al. 2020; Zhu et al. 2020). So far, this virus has spread to all areas of China and even to other countries. The epidemic has caused 67,102 confirmed infections with 1526 fatal cases     

Comparative morphology of the carpel in the Liliaceae: Hewardieae, Petrosavieae, and Tricyrteae

The young pistils in the melanthioid tribes, Hewardieae, Petrosavieae and Tricyrteae, are uniformly tricarpellate and syncarpous. They lack raphide idioblasts. All are multiovulate, with bitegmic ovules. The Petrosavieae are marked by the presence of septal glands and incomplete syncarpy. Tepals and stamens adhere to the ovary in the Hewardieae and the Petrosavieae but not in the Tricyrteae. Two vascular bundles occur in the stamens of the Hewartlieae and Tricyrtis latifolia. Ventral bundles in the upper part of the ovary of the Hewardieae are continuous with compound septal bundles and placental bundles in the lower part. Putative ventral bundles occur in the alternate position in the Tricyrteae and putative placental bundles in the opposite. position in the Petrosavieae. The dichtomously branched stigma in each carpel of the Tricyrteae is supplied by a bifurcated dorsal bundle.     

Entwicklungsgeschichte und Ultrastruktur von Pollenkitt und Exine bei nahe verwandten entomophilen und anemophilen Angiospermensippen derAlismataceae,Liliaceae, Juncaceae,Cyperaceae, Poaceae undAraceae

Some closely related members of the monocotyledonous familiesAlismataceae, Liliaceae, Juncaceae, Cyperaceae, Poaceae andAraceae with variable modes of pollination (insect- and wind-pollination) were studied in relation to the ultrastructure of pollenkitt and exine (amount, consistency and distribution of pollenkitt on the surface of pollen grains). The character syndromes of pollen cementing in entomophilous, anemophilous and intermediate (ambophilous or amphiphilous) monocotyledons are the same in principal as in dicotyledons. Comparing present with former results one can summarize: 1) The pollenkitt is always produced in the same manner by the anther tapetum in all angiosperm sub-classes. 2) The variable stickiness of entomophilous and anemophilous pollen always depends on the particular distribution and consistency of the pollenkitt, but not its amount on the pollen surface. 3) The mostly dry and powdery pollen of anemophilous plants always contains a variable amount of inactive pollenkitt in its exine cavities. 4) A step-by step change of the pollen cementing syndrome can be observed from entomophily towards anemophily. 5) From the omnipresence of pollenkitt in all wind-pollinated angiosperms studied one can conclude that the ancestors of anemophilous angiosperms probably have been zoophilous (i.e. entomophilous) throughout.

     

Identification and Characterization of the First Equine Parainfluenza Virus 5

正Dear Editor,Parainfluenza virus 5 (PIV5), known as canine parainfluenza virus in the veterinary field, is a negative-sense,nonsegmented, single-stranded RNA virus belonging to the Paramyxoviridae family (Chen 2018). The virus was first reported in primary monkey kidney cells in 1954 (Hsiung1972), then it has been frequently discovered in various     

Pathogenic Characterization and Full Length Genome Sequence of a Reassortant Infectious Bursal Disease Virus Newly Isolated in Pakistan

<正>Dear Editor,Infectious bursal disease (IBD) is one of the most important diseases of the poultry. The IBD virus (IBDV), a nonenveloped virus belonging to the Birnaviridae family with a genome consisting of two segments of double-stranded RNA (segments A and B), targets B lymphocytes of bursa of Fabricious leading to immunosuppression. In Pakistan,poultry farming is the second biggest industry and IBD is the second biggest disease threating the poultry sector.However, there is limited genome information of IBDV