Article(id=1228017372846551344, tenantId=1146029695717560320, journalId=1192105938417971205, issueId=1228017371202388759, articleNumber=null, orderNo=null, doi=10.13343/j.cnki.wsxb.20240631, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1728835200000, receivedDateStr=2024-10-14, revisedDate=null, revisedDateStr=null, acceptedDate=1732464000000, acceptedDateStr=2024-11-25, onlineDate=1770711757145, onlineDateStr=2026-02-10, pubDate=1741017600000, pubDateStr=2025-03-04, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1770711757145, onlineIssueDateStr=2026-02-10, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1770711757145, creator=13701087609, updateTime=1770711757145, updator=13701087609, issue=Issue{id=1228017371202388759, tenantId=1146029695717560320, journalId=1192105938417971205, year='2025', volume='65', issue='3', pageStart='871', pageEnd='1336', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1770711756754, creator=13701087609, updateTime=1770719134572, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1228048316089434941, tenantId=1146029695717560320, journalId=1192105938417971205, issueId=1228017371202388759, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1228048316093629246, tenantId=1146029695717560320, journalId=1192105938417971205, issueId=1228017371202388759, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1007, endPage=1016, ext={EN=ArticleExt(id=1228017373261787445, articleId=1228017372846551344, tenantId=1146029695717560320, journalId=1192105938417971205, language=EN, title=Toxin-antitoxin system resists phage infection: a review, columnId=1192149543727808575, journalTitle=Acta Microbiologica Sinica, columnName=Review, runingTitle=null, highlight=null, articleAbstract=

The toxin-antitoxin (TA) system is ubiquitous in bacteria and archaea. A typical TA system generally consists of a toxin that inhibits bacterial growth and an antitoxin that neutralizes toxin toxicity. At present, TA systems are classified into types I-VIII, of which type II system is the most extensively studied. In addition, researchers have found that there are atypical TA systems such as monocistronic TA systems and three-component TA systems. After the discovery of the first TA system (CcdB/CcdA) in the 1980s, TA systems have been shown to play a key role in the physiological processes of microorganisms. In this paper, we review the research results about the roles of TA systems in resisting bacteriophage infections in recent years and summarize the neutralization mechanisms. In particular, we brief how TA systems specifically sense the invading bacteriophages and the underlying molecular mechanisms, aiming to provide reference for the research on the roles and regulation mechanisms of unknown TA systems in the future.

, correspAuthors=Xurong WANG, authorNote=null, correspAuthorsNote=
*E-mail:
, copyrightStatement=null, copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Qingjian ZHU, Songying OUYANG, Xurong WANG), CN=ArticleExt(id=1228017375631569242, articleId=1228017372846551344, tenantId=1146029695717560320, journalId=1192105938417971205, language=CN, title=毒素-抗毒素系统抵抗噬菌体感染研究进展, columnId=1192149543882997826, journalTitle=微生物学报, columnName=综述, runingTitle=null, highlight=null, articleAbstract=

毒素-抗毒素(toxin-antitoxin, TA)系统广泛分布于细菌和古菌中。TA系统通常由一个能够抑制细菌生长的毒素和一个能够中和毒素毒性的抗毒素组成。目前,TA系统分为I-VIII型,其中II型TA系统的研究最为深入。然而,近年来也发现了一些非典型TA系统,如单顺反子TA系统和三组分TA系统等。自20世纪80年代发现首个TA系统(CcdB/CcdA)以来,TA系统被认为在微生物的多种生理过程中发挥重要功能。本文综述了近年来TA系统在抵抗噬菌体感染方面的功能,特别是TA系统如何特异性感知入侵噬菌体及其分子机制,旨在为探索未知TA系统的生物功能及调控机制提供参考。

, correspAuthors=王勖荣, authorNote=null, correspAuthorsNote=null, copyrightStatement=null, copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=t3uOuk9H6douedcqz5Jrhg==, magXml=qHXaQJBkR3/vVhe4hUn8Rw==, pdfUrl=null, pdf=zn8PrkFOWU2gS33jllcuKA==, pdfFileSize=1456829, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=HVKMJIGscYXPTF7YPuXl7A==, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=KyCSiNK0BZkxH9gXJfbXxw==, mapNumber=null, authorCompany=null, fund=null, authors=

作者贡献声明

朱青健:负责论文的撰写与修改;欧阳松应:对论文进行了审阅;王勖荣:负责绘图工作并汇总了相关文献。

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毒素-抗毒素系统抵抗噬菌体感染研究进展
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朱青健 1 , 欧阳松应 1, 2 , 王勖荣 1, *
微生物学报 | 综述 2025,65(3): 1007-1016
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微生物学报 | 综述 2025, 65(3): 1007-1016
毒素-抗毒素系统抵抗噬菌体感染研究进展
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朱青健1, 欧阳松应1, 2, 王勖荣1, *
作者信息
  • 1 福建师范大学 生命科学学院,福建 福州
  • 2 福建师范大学,南方生物医学研究中心,福建 福州
Toxin-antitoxin system resists phage infection: a review
Qingjian ZHU1, Songying OUYANG1, 2, Xurong WANG1, *
Affiliations
  • 1 College of Life Science, Fujian Normal University, Fuzhou, Fujian, China
  • 2 FJNU Biomedical Research Center of South China, Fujian Normal University, Fuzhou, Fujian, China
出版时间: 2025-03-04 doi: 10.13343/j.cnki.wsxb.20240631
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毒素-抗毒素(toxin-antitoxin, TA)系统广泛分布于细菌和古菌中。TA系统通常由一个能够抑制细菌生长的毒素和一个能够中和毒素毒性的抗毒素组成。目前,TA系统分为I-VIII型,其中II型TA系统的研究最为深入。然而,近年来也发现了一些非典型TA系统,如单顺反子TA系统和三组分TA系统等。自20世纪80年代发现首个TA系统(CcdB/CcdA)以来,TA系统被认为在微生物的多种生理过程中发挥重要功能。本文综述了近年来TA系统在抵抗噬菌体感染方面的功能,特别是TA系统如何特异性感知入侵噬菌体及其分子机制,旨在为探索未知TA系统的生物功能及调控机制提供参考。

毒素-抗毒素  /  中和机制  /  噬菌体  /  模式识别受体

The toxin-antitoxin (TA) system is ubiquitous in bacteria and archaea. A typical TA system generally consists of a toxin that inhibits bacterial growth and an antitoxin that neutralizes toxin toxicity. At present, TA systems are classified into types I-VIII, of which type II system is the most extensively studied. In addition, researchers have found that there are atypical TA systems such as monocistronic TA systems and three-component TA systems. After the discovery of the first TA system (CcdB/CcdA) in the 1980s, TA systems have been shown to play a key role in the physiological processes of microorganisms. In this paper, we review the research results about the roles of TA systems in resisting bacteriophage infections in recent years and summarize the neutralization mechanisms. In particular, we brief how TA systems specifically sense the invading bacteriophages and the underlying molecular mechanisms, aiming to provide reference for the research on the roles and regulation mechanisms of unknown TA systems in the future.

toxin-antitoxin  /  neutralization mechanism  /  bacteriophage  /  pattern recognition receptor
朱青健, 欧阳松应, 王勖荣. 毒素-抗毒素系统抵抗噬菌体感染研究进展. 微生物学报, 2025 , 65 (3) : 1007 -1016 . DOI: 10.13343/j.cnki.wsxb.20240631
Qingjian ZHU, Songying OUYANG, Xurong WANG. Toxin-antitoxin system resists phage infection: a review[J]. Acta Microbiologica Sinica, 2025 , 65 (3) : 1007 -1016 . DOI: 10.13343/j.cnki.wsxb.20240631
毒素-抗毒素(toxin-antitoxin, TA)系统广泛存在于原核生物基因组中,特别是在细菌和古菌中,其中毒素能够降低细菌的代谢从而抑制其生长,而抗毒素可以通过精巧的方式解除毒素对细菌生长的抑制,截至目前,根据抗毒素的性质及其中和毒素的方式,TA系统已被分为I-VIII型[1]。TA系统被认为在细菌的生命活动中的许多方面发挥着重要的功能[2],尽管其生物学功能在某些方面仍存在争议。目前,TA系统在维持质粒稳定性[3]和抵御噬菌体感染[4]方面的功能已得到普遍认可,特别是近年来,多个新颖的TA系统被报道能够直接识别并响应噬菌体感染,这些研究极大地推进了人们对TA系统介导的抗噬菌体感染功能的认识。因此,本文聚焦于TA系统在抗噬菌体功能方面的研究进展,尤其是最新报道的关于TA系统中的识别受体,以一种类似于真核先天免疫系统中“病原体相关分子模式”的方式感知并响应病毒入侵的分子机制。
TA系统通常由一个毒素和对应的抗毒素组成,人们根据抗毒素的性质(蛋白质或RNA)及毒素被中和的方式,将TA系统分为I-VIII型[1]。随着研究的深入,还发现了一些非经典的TA系统。
TA系统被分为I-VIII型[1]。在I型TA系统中,毒素主要是破坏细菌膜完整性的疏水短肽,这会阻碍膜电位和细胞分裂[5],而抗毒素是反义RNA,通过与编码毒素的mRNA结合来抑制毒素的转录,从而中和其毒性[6]。II型TA系统中的毒素和抗毒素都是蛋白质,抗毒素通常与毒素直接形成蛋白质-蛋白质复合物来抑制毒素的毒性;例如,含RES结构域的毒素ParT通过水解细胞内的NAD+导致细菌死亡,而抗毒素ParS可以直接与ParT相互作用,抑制其酶活性[7]。III型TA系统中的毒素一般为核酸内切酶,抗毒素则是RNA[8]。首个III型TA系统是在植物病原菌黑腐果胶杆菌(Pectobacterium atrosepticum)的质粒中发现的[9]。在Ⅳ型TA系统中,抗毒素和毒素均为蛋白质,但它们之间不存在直接相互作用。然而,抗毒素能够通过干扰毒素与底物的结合,来调节毒素的毒性[10]。GhoT-GhoS是目前唯一报道的V型TA系统,其中毒素GhoT通过破坏细胞膜,使宿主进入生长停滞状态,而抗毒素GhoS能够靶向GhoT的mRNA并进行切割[11]。在VI型TA系统中,毒素SocB通过抑制DNA复制的延伸来抑制细胞活性,而抗毒素SocA则促使毒素SocB被蛋白酶ClpXP降解[12]。VII型TA系统中的抗毒素不同于II型TA系统中的转录因子,它具有酶的功能,通过对毒素进行翻译后修饰(如磷酸化、腺苷酸化等)来中和其毒性[13]。VIII型TA系统中的毒素与抗毒素均为RNA,毒素的活性主要是阻断tRNA或抑制mRNA靶标,而抗毒素则通过抑制毒素的转录来中和其毒性[14]
除了如RnlAB、DarTG等二元TA系统外,还发现了一些非经典的TA系统,包括三组分TA系统和单顺反子TA系统[15]等。例如,属于单顺反子TA系统的CapRelSJ46,其N端作为毒素可以利用ATP和GTP合成焦磷酸腺苷(pyrophosphate adenosine, ppApp),导致细胞内ppApp的过度积累并影响蛋白质合成,从而使细菌生长停滞[16]。三组分TA系统则除了已有的毒素和同源抗毒素外,还附带一个额外的组分。例如,ω-ε-ζ就是一个典型的三组分TA系统,起初ε-ζ被定义为经典的Ⅱ型TA系统,其中ζ作为毒素,是一种蛋白激酶,可以特异性磷酸化细胞壁合成的前体尿苷二磷酸N-乙酰基-d-葡糖胺(urine N-acetyl-β-d-glucosaminidase, UNAG),生成尿苷二磷酸N-乙酰葡萄糖胺-3-磷酸(uridine diphosphate N-acetylglucosamine 3-phosphate,UNAG-3P),该产物可作为肽聚糖前体合成酶的竞争性抑制剂,导致肽聚糖的生物合成受损,同时毒素ζ也可以抑制磷壁酸的合成[17]。第3个组分ω虽然未直接参与该过程,但ε通过阻止毒素ζ与ATP的结合来抑制其活性,起到整体调节的作用[18]。最近,通过分析大肠杆菌HipBA的多样性,发现了HipBST TA系统[19]。HipT和HipS分别与大肠杆菌毒素HipA的C端和N端约有20%的一致性,然而HipT和HipS却分别作为毒素和抗毒素发挥功能[20]
尽管TA系统在生物中广泛存在,但目前对TA系统功能的研究仍不够清晰。一些研究表明,TA系统在促进微生物抗逆性、维持基因组稳定性、抵抗噬菌体感染[21]和促进细菌程序性死亡[22]等方面均发挥作用。然而,除了维持质粒稳定性和抵抗噬菌体感染外,目前对于TA系统的其他功能仍存在争议。例如,最近发现的大肠杆菌MqsR/MqsA TA系统中,敲除mqsRA并未引起转录的显著变化,这挑战了MqsR/MqsATA系统在抗胁迫中作用的传统观点[23]。因此,本文仅介绍TA系统在维持质粒稳定性和抗噬菌体方面的研究进展。
F质粒上的CcdA/CcdB是首个被鉴定的TA系统[24],它对质粒的稳定性至关重要。CcdA作为一种抗毒素相对不稳定,需要不断重新合成以抑制毒素CcdB的活性。CcdB作为毒素是一种解旋酶抑制剂,而Gyrase是一种促解旋酶。毒素通过抑制该酶进而影响DNA的复制,最终导致细胞死亡[25]。如果质粒未携带CcdAB,则抗毒素不能持续得到补充,毒素CcdB会从Ccd-AB蛋白复合物中脱离并发挥其毒性[26]。I型TA系统Hok/Sok也对R1质粒的稳定性起到重要作用[27]
在生物在进化过程中,细菌产生了许多自我保护和防御机制来抵抗噬菌体感染。除了CRISPR-Cas系统和限制性修饰系统外,近年来还发现了包括TA系统在内的许多新颖的抗噬菌体系统。
尽管早在1996年就已发现TA系统可以抵抗噬菌体感染[28],但关于TA系统如何感知噬菌体的侵染尚不清楚,最近报道的CapRelSJ46、PARIS等多个TA系统可以直接识别噬菌体的特异成分,在噬菌体感染时激活TA系统来抵御感染,从而将TA系统与抗噬菌体功能直接联系起来。
RnlAB属于Ⅱ型TA系统,其中毒素RnlA曾称作为Rnase LS,具有核糖核酸内切酶功能[29],能够靶向并降解编码腺苷酸环化酶的mRNA,从而降低cyaA基因的表达[30]。抗毒素RnlB可以与RnlA直接结合,解除其毒性[31]
最新研究表明,RnlA是一种高等真核生物和原核生物核苷酸结合(higher eukaryotes and prokaryotes nucleotide binding, HEPN)蛋白,包含N端结构域(N-terminal domain, NTD)、N末端重复结构域(N-terminal repetitive domain, NRD)和C端负责与Dmd识别的结构域(Dmd-binding domain, DBD);其中NTD对底物的结合至关重要,C端结构域具有典型的HEPN核酸酶折叠,在无底物或无抗毒素RnlB结合的情况下,RnlA以非经典二聚态形式存在,抗毒素RnlB结合在HEPN二聚体界面,由1个RnlA二聚体与2个单体RnlB分子相互作用形成复合物,阻止底物接近RX4H的酶活中心,从而抑制RnlA的毒性;当噬菌体感染时,抗毒素RnlB会快速降解,导致毒素RnlA释放,激活核糖核酸内切酶活性,降解噬菌体mRNA[32]
RnlAB能够通过流产感染(abortive infection, Abi)的方式应对Dmd突变的T4噬菌体。所谓流产感染,是指噬菌体感染细菌时,诱导细菌 “自杀”,使病毒复制被中断或无法继续进行,从而防止噬菌体扩散并感染更多 “细菌”[33]。毒素RnlA的活性在T4噬菌体感染后增强,它能快速降解T4噬菌体晚期基因的mRNA,阻止这些基因的表达,从而阻止T4噬菌体的感染[34]。当T4 dmd突变的噬菌体感染时,抗毒素RnlB被快速ClpXP蛋白酶降解,导致毒素RnlA激活,而具有核酸内切酶活性的毒素RnlA可导致T4噬菌体晚期mRNA降解,阻止T4噬菌体的传染(图1)。相比之下,T4噬菌体可以感染大肠杆菌,是因为噬菌体编码的Dmd可作为抗毒素,结合并抑制毒素RnlA的活性,这意味着噬菌体可以编码具有抗毒素功能的蛋白质,与宿主的毒素结合,进而有利于噬菌体的感染[35]
ToxIN是一个研究较为清晰的III型TA系统,其中毒素ToxN具有核酸内切酶活性,而抗毒素为一系列短串联重复序列的RNA[36]。通过X-射线晶体学解析的大肠杆菌ToxN的结构发现抗毒素ToxI是一个36 nt的RNA假结(pseudoknot),并且3个抗毒素ToxI会与3个毒素ToxN通过广泛的蛋白质-RNA相互作用,组装成一个三聚体的ToxN-ToxI复合物[37]
Fineran等[38]研究结果表明,革兰氏阴性菌胡萝卜软腐坚固杆菌(Pectobacterium carotovorum)的toxIN系统可以通过Abi机制为植物病原体提供对噬菌体ΦA2和ΦM1的有效抗性保护。最近研究发现,大肠杆菌III型TA系统中的toxIN具有抗噬菌体功能,通过RNA测序技术发现,毒素toxN在T4噬菌体生活周期的晚期被激活,ToxN主要通过直接切割病毒而非宿主的mRNA来阻止噬菌体感染;因此,ToxN不会像典型的Abi系统那样引发细胞死亡,而是阻断成熟病毒颗粒的产生[39]。在T4-like噬菌体中,基因tifA能够阻止toxIN TA系统介导的抗噬菌体功能,最近发现TifA能够直接与具有核酸内切酶活性的毒素ToxN和抗毒素RNA结合,此外,TifA可以结合RNA,因此将与毒素ToxN捕获细胞内的RNA,特别是16S rRNA基因,从而形成一个高分子量的蛋白质- RNA复合物,并使毒素ToxN处于失活状态[40]
DarTG是一类在多种微生物中广泛分布的TA系统,首次在结核分枝杆菌中被发现[41]。其中毒素DarT有一个DUF4433结构域,具有ADP-核糖基转移酶(ADP-ribosyltransferase, ADPRT)活性。然而,与真核细胞中ART将NAD+上的ADP-核糖基转移到蛋白质上不同,DarT毒素以序列特异性的方式对单链DNA的胸腺嘧啶进行ADP-核糖基化修饰,从而影响DNA的复制,并导致RecA水平升高;抗毒素DarG具有一个特殊结构域,一方面可以与毒素DarT直接互作,另一方面也能够逆转毒素介导的ADP-核糖基化修饰,以双重方式中和毒素毒性[42]。来自大肠埃希氏菌(Escherichia coli)的DarTG与结核的DarTG有一定类似之处,但抗毒素DarG以2种不同的模式中和毒素的毒性:一方面通过N端结构域去除DNA上的ADP-核糖基,另一方面还可以通过抗毒素的C端将毒素进行物理隔绝[43]
最近,通过生物信息学在微生物基因组的其他防御系统附近发现了与DarTG同源的2个TA系统,即DarTG1和DarTG2;这2个TA系统中,毒素DarT都是ADP-核糖基转移酶家族蛋白,而抗毒素属于不同的蛋白质家族;其中,DarG1具有一个YbiA家族蛋白,而DarG2的N端则有一个macrodomain结构域;研究表明RB69和T5噬菌体的感染会使毒素DarT快速释放,进而导致噬菌体DNA的ADP-核糖基化修饰,阻止病毒复制,进一步影响成熟噬菌体颗粒的产生[44]。通过对噬菌体感染后的细菌的DNA进行深度测序,发现70%被核糖基化修饰的DNA来自噬菌体,并发现毒素DarT1能阻止噬菌体的复制和噬菌体新DNA的积累[45]
DarT家族被证明在细胞中进行过表达可以使单链DNA (single-stranded DNA, ssDNA)发生腺苷核糖基化修饰;DarT作为一种毒素,具有ADP核糖转移酶活性,在激活后可以通过将细胞内的DNA进行ADP核糖基化,阻断噬菌体双链DNA (double-stranded DNA, dsDNA)的复制[46]。Groslambert等[47]研究表明,DarT毒素不是在DNA复制的起始阶段发挥作用,而是在延伸过程中抑制DNA的复制,而DarG作为抗毒素,具有ADP-水解酶活性,可以将毒素DarT对底物的修饰进行逆转,类似于磷酸化修饰与去磷酸化修饰乙酰化修饰、去乙酰化修饰等。
虽然上述TA系统被证明在抵御噬菌体感染过程中发挥重要功能,但对于这些TA系统如何感知噬菌体的入侵并导致TA系统的激活(毒素从复合物的释放)尚不清楚。CapRelSJ46是首个报道的能够直接以类似真核生物病原体相关分子模式(pathogen-associated molecular patterns, PAMPs)方式识别噬菌体编码的主要衣壳蛋白(major capsid protein, MCP)的TA系统[48]。CapRelSJ46属于近年来新发现的一类toxSAS毒素-抗毒素系统,在toxSAS TA系统中毒素是RHS家族蛋白,具有一个合成“报警信号”(alarmone)的结构域,它可以通过消耗ATP,合成ppApp抑制细菌生长[49];毒素也可以将ATP的焦磷酸转移到tRNA上,对其进行焦磷酸化修饰,这将导致蛋白质翻译功能的抑制。已报道的几个toxSAS TA系统中,翻译抑制介导的toxSAS TA系统中,抗毒素ATfaRel2的ZFP结构域能够阻止ATP进入FaRel2毒素的焦磷酸盐供体位点;而产生ppApp报警信号的toxSAS TA系统中,Tis1抗毒素占据了焦磷酸盐受体结合位点[50]
CapRelSJ46由单个开放阅读框编码的系统组成,是一个毒素与抗毒素融合形式的TA系统,CapRelSJ46的晶体结构解析表明,其N端是一个保守的核苷酸焦磷酸激酶结构域,该结构域存在于alarmone合成酶和tRNA-焦磷酸转移酶中,发挥毒素作用;而C端起到抗毒素的功能,并且与细菌信号素分子合成酶(bacterial alarmone synthetase, SAS)具有同源性,进而合成alarmone ppApp,这类蛋白是最近新发现的一类广泛存在的TA系统,其中毒素能够将ATP上的焦磷酸转移到tRNA的3′-CCA[51],从而抑制tRNA的氨基酰化和核糖体相关RSH-RelA对细胞氨基酸饥饿的感知,抑制蛋白质的合成(图2)。
CapRelSJ46除了能够与SECƟ27噬菌体编码的MCP结合、解除C端抗毒素的抑制之外,来自同一个实验室的最新研究发现,Bas11噬菌体具有2个trigger,可以激活CapRelSJ46,CapRelSJ46能够通过相互重叠但又不完全相同的sensor区域直接结合和感知与MCP完全不相关、功能和结构完全不同的噬菌体的Gp54[52]
毒素-抗毒素-分子伴侣(toxin-antitoxin-chaperone, TAC)系统由一个HigBA类型的Ⅱ型 TA系统和一个分子伴侣SecB组成,在该系统中,毒素HigB是一个核糖体依赖的核糖核酸酶(ribonuclease),能够切割核糖体A位点结合的mRNA,从而抑制蛋白质合成,而抗毒素的中和作用则依赖于HigBA和SecB的共同作用[53]。最近,研究发现了属于TAC系统的具有抗噬菌体功能的TA系统,在无噬菌体感染时,分子伴侣SecB能够维持抗毒素的稳定性,从而抑制毒素毒性;遇到噬菌体感染后,SecB会通过降解抗毒素来激发毒素的活性,从而阻止噬菌体的繁殖[54]。最近的研究揭示了E. coli NT1F31中的HigBAC TA系统发挥抗噬菌体感染的分子机制,与MtbTAC中的MtbSecB分子伴侣类似,HigBAC中的SecB通过芳香族特异性识别模式来识别用于稳定抗毒素的“分子伴侣成瘾”区域(chaperone addiction, ChAD),该区域位于抗毒素的C端[55]。当受到噬菌体感染时,HigBAC系统可以识别噬菌体的主要尾部蛋白gpV,由于分子伴侣HigC以相似的方式结合gpV与ChAD,噬菌体的gpV会竞争性地结合抗毒素的ChAD,导致抗毒素不能与分子伴侣HigC结合,从而发生降解,这一过程会激活HigB毒素的活性,通过影响翻译来阻碍噬菌体的繁殖(图3)[56]
除了HigBAC之外,CmdTAC也属于TAC系统。来自大肠杆菌ECOR22的CmdTAC (也称PD-T4-9)中,毒素CmdT是一个具有HYE家族ADP-核糖基转移酶功能的效应蛋白,而抗毒素为CmdA,在该TA系统中,分子伴侣样的CmdC作为感知噬菌体衣壳蛋白的感应器,当噬菌体感染发生时,新合成的T4噬菌体的衣壳蛋白会被CmdC感知,从而触发CmdC从CmdTAC中分离出来,导致该TA系统的不稳定和抗毒素CmdA的降解,最终导致具有ADP-核糖基转移酶活性的毒素的释放[57]
细菌噬菌体抗限制诱导系统(phage anti-restriction-induced system, PARIS)是最近被鉴定的位于细菌基因组的防御岛的抗噬菌体系统,它存在于整合到宿主大肠杆菌基因组中的P4样噬菌体卫星位点;PARIS包含1个SMC家族ATPase蛋白AriA和1个金属依赖的TOPRIM/OLD家族核酸酶,先前的研究表明,T7噬菌体的Ocr的错义突变可以使其逃逸细菌的PARIS免疫系统[58]。最新的研究结果表明,PARIS能被T7噬菌体编码的蛋白质Ocr激活,Ocr富含带负电荷的氨基酸,已被证明能够模拟DNA,在I型限制修饰系统和BREX防御系统中,Ocr可以抑制它们的抗噬菌体功能[59]。PARIS中的AriA和AriB对于其抗噬菌体功能都是必需的,通过Pull-down实验发现,AriA的ATPase活性对于AriA和AriB的组装至关重要,而对于AriB的分离则无影响;AriA与Ocr的结合会极大地降低其ATPase活性,但如果AriA结合ATP的Walker A发生突变,则会影响AriA与Ocr的结合[60]
最近的研究还发现,PARIS属于II型TA系统,其中AriA作为抗毒素,而AriB则充当毒素的角色,在未受到噬菌体感染时,由于AriA的结合,毒素AriB处于无活性状态,研究人员通过冷冻电镜解析了PARIS系统的结构,发现单独的AriA以六聚体形式存在,而AriA和AriB会组装成一个比例为6:3的类似水母状的复合物,从而维持其无活性状态;与AirA分离的毒素AirB可降解宿主赖氨酸tRNA (tRNALys),从而阻断蛋白质翻译过程,导致细菌生长停滞或细胞死亡[61]。另外,T5噬菌体却可以表达一个tRNALys的突变体,因此这个突变体不被PARIS切割,从而能够逃避PARIS TA系统提供的免疫保护[62]
研究发现,TA系统在致病微生物中的分布较为广泛,且与微生物的致病性密切相关,这一特性引起了众多微生物学家及医药学界的广泛关注。特别是本文重点阐述的TA系统,能够直接感知并响应噬菌体的存在,从而发挥强大的抗噬菌体功能。噬菌体能够特异性杀死细菌,而不引起细菌的耐药性的产生,被视为抗生素的一个替代方案。然而,细菌体内所携带的如TA系统、CRISPR-Cas等免疫系统,会对噬菌体产生显著影响,可以被用于工业上,开发防止噬菌体感染的发酵菌株[63]。因此,对TA系统机制进行深入研究,不仅有助于进一步理解细菌的防御机制,还可为设计高效的噬菌体制剂提供理论基础和新思路,同时为解决工业上的噬菌体污染等问题开辟新的途径。
  • 国家自然科学基金(32300035)
  • 福建省自然科学基金(2023J0123)
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doi: 10.13343/j.cnki.wsxb.20240631
  • 接收时间:2024-10-14
  • 首发时间:2026-02-10
  • 出版时间:2025-03-04
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  • 收稿日期:2024-10-14
  • 录用日期:2024-11-25
基金
National Natural Science Foundation of China(32300035)
国家自然科学基金(32300035)
Fujian Provincial Natural Science Foundation(2023J0123)
福建省自然科学基金(2023J0123)
作者信息
    1 福建师范大学 生命科学学院,福建 福州
    2 福建师范大学,南方生物医学研究中心,福建 福州

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2种不同金属材料的力学参数

Family
属数
Number of
genus
种数
Number of
species
占总种数比例
Percentage of
total species (%)

Genus
种数
Number of
species
占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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