阻断翻译的mRNA ADP核糖基转移酶的抗病毒防御-动脉网

Anti-viral defence by an mRNA ADP-ribosyltransferase that blocks translation

Nature 等信源发布 2024-10-23 22:39

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AbstractHost–pathogen conflicts are crucibles of molecular innovation1,2. Selection for immunity to pathogens has driven the evolution of sophisticated immunity mechanisms throughout biology, including in bacterial defence against bacteriophages3. Here we characterize the widely distributed anti-phage defence system CmdTAC, which provides robust defence against infection by the T-even family of phages4.

摘要宿主-病原体冲突是分子创新的熔炉1,2。对病原体免疫的选择推动了整个生物学中复杂免疫机制的进化，包括细菌防御噬菌体3。在这里，我们描述了广泛分布的抗噬菌体防御系统CmdTAC，它提供了针对T-even噬菌体家族感染的强大防御4。

Our results support a model in which CmdC detects infection by sensing viral capsid proteins, ultimately leading to the activation of a toxic ADP-ribosyltransferase effector protein, CmdT. We show that newly synthesized capsid protein triggers dissociation of the chaperone CmdC from the CmdTAC complex, leading to destabilization and degradation of the antitoxin CmdA, with consequent liberation of the CmdT ADP-ribosyltransferase.

我们的研究结果支持CmdC通过检测病毒衣壳蛋白来检测感染的模型，最终导致毒性ADP-核糖基转移酶效应蛋白CmdT的激活。我们显示，新合成的衣壳蛋白触发伴侣CmdC与CmdTAC复合物的解离，导致抗毒素CmdA的不稳定和降解，从而释放CmdT ADP核糖基转移酶。

Notably, CmdT does not target a protein, DNA or structured RNA, the known targets of other ADP-ribosyltransferases. Instead, CmdT modifies the N6 position of adenine in GA dinucleotides within single-stranded RNAs, leading to arrest of mRNA translation and inhibition of viral replication. Our work reveals a novel mechanism of anti-viral defence and a previously unknown but broadly distributed class of ADP-ribosyltransferases that target mRNA..

值得注意的是，CmdT不靶向蛋白质，DNA或结构化RNA，这是其他ADP-核糖基转移酶的已知靶标。相反，CmdT修饰单链RNA中GA二核苷酸中腺嘌呤的N6位置，导致mRNA翻译停滞和病毒复制抑制。我们的工作揭示了一种新的抗病毒防御机制，以及一类以前未知但分布广泛的靶向mRNA的ADP核糖基转移酶。。

MainADP-ribosyltransferases are important enzymes found throughout biology that transfer the ADP ribose moiety of NAD+ onto other biomolecules, usually modifying an amino acid on a target protein5,6,7. ADP-ribosylation is one of the most common post-translational modifications in biology, and is used to regulate a wide variety of proteins involved in cellular signalling, chromatin and transcription, DNA repair, and other functions.

MainADP-核糖基转移酶是整个生物学中发现的重要酶，可将NAD+的ADP-核糖部分转移到其他生物分子上，通常修饰靶蛋白上的氨基酸5,6,7。ADP-核糖基化是生物学中最常见的翻译后修饰之一，用于调节涉及细胞信号传导，染色质和转录，DNA修复和其他功能的多种蛋白质。

At least six of the human ADP-ribosyltransferases (previously called poly-ADP-ribosyl polymerases8 (PARPs)) are induced by interferon and are thus hypothesized to function in anti-viral defence9,10, but their precise roles and targets remain poorly defined. Although they have been studied for decades as protein modifiers, recent work has identified ADP-ribosyltransferases that target nucleic acids.

至少有六种人类ADP-核糖基转移酶（以前称为聚ADP-核糖基聚合酶8（PARPs））是由干扰素诱导的，因此被假设在抗病毒防御中起作用9,10，但它们的确切作用和靶标仍然不明确。尽管它们作为蛋白质修饰剂已经研究了数十年，但最近的工作已经确定了靶向核酸的ADP-核糖基转移酶。

DarT toxins of DarTG toxin–antitoxin systems can modify single-stranded DNA11. The Pseudomonas aeruginosa type VI secretion effector RhsP2 targets the 2′ hydroxyl of some double-stranded RNAs12, and in Photorhabdus laumondii, a type VI secretion effector modifies 23S ribosomal RNA13 (rRNA).Here, we identify CmdT, an ADP-ribosyltransferase that functions in bacterial anti-phage defence by specifically modifying mRNAs to block phage translation and the production of mature virions.

DarTG毒素-抗毒素系统的DarT毒素可以修饰单链DNA11。铜绿假单胞菌VI型分泌效应子RhsP2靶向一些双链RNAs12的2'羟基，而在月桂光杆菌中，VI型分泌效应子修饰23S核糖体RNA13（rRNA）。在这里，我们确定了CmdT，一种ADP-核糖基转移酶，通过特异性修饰mRNA来阻断噬菌体翻译和成熟病毒粒子的产生，从而在细菌抗噬菌体防御中发挥作用。

CmdT is part of a tripartite toxin–antitoxin–chaperone (TAC) system. Toxin–antitoxin systems have a major role in anti-phage defence14. These systems feature a protein toxin that is restrained from killing a cell or blocking cell growth by a cognate antitoxin15. For anti-phage toxin–antitoxin systems, phage infection must somehow liberate the toxin, but the mechanisms responsible remain incompletely understood16.

CmdT是三方毒素-抗毒素-伴侣（TAC）系统的一部分。毒素-抗毒素系统在抗噬菌体防御中起主要作用14。这些系统的特征是蛋白质毒素被同源抗毒素抑制杀死细胞或阻断细胞生长15。。

TAC systems are common variants that feature a chaperone rel.

TAC系统是具有伴侣rel的常见变体。

Data availability

数据可用性

Summary spectra and raw data for IP–MS/MS of CmdC and CmdT pulldowns were deposited at MassIVE and can be accessed under accession MSV000093692; a summary table of high confidence hits is provided as Supplementary Table 1. Raw data for nucleotide MS and ESI-MS/MS were deposited at MassIVE and can be accessed under accession MSV000093878.

CmdC和CmdT下拉列表的IP-MS/MS的摘要光谱和原始数据已大量保存，可以在登录号MSV000093692下访问；补充表1提供了高可信度命中的汇总表。核苷酸MS和ESI-MS/MS的原始数据大量保存，可以在登录号MSV000093878下访问。

RNA-seq and RIP–seq data are available at GEO under accession number GSE253514. All other data are available in the manuscript or the supplementary materials. Source data are provided with this paper..

RNA-seq和RIP-seq数据可在GEO获得，登录号为GSE253514。所有其他数据均可在手稿或补充材料中找到。本文提供了源数据。。

Code availability

代码可用性

Code used for RNA-seq and in vivo RIP–seq analysis is available at https://doi.org/10.5281/zenodo.10522487 (ref. 58).

用于RNA-seq和体内RIP-seq分析的代码可在https://doi.org/10.5281/zenodo.10522487（参考文献58）。

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Doering, C. Anti-viral defense by an ADP-ribosyltransferase that targets mRNA to block translation. Zenodo https://doi.org/10.5281/zenodo.10522488 (2024).Download referencesAcknowledgementsThe authors thank D. Saxton, T. Zhang, S. Srikant and C. Beck for comments on the manuscript; B.

Doering，C。通过靶向mRNA以阻断翻译的ADP-核糖基转移酶进行抗病毒防御。泽诺多https://doi.org/10.5281/zenodo.10522488（2024年）。下载参考文献致谢作者感谢D.Saxton，T.Zhang，S.Srikant和C.Beck对手稿的评论；B。

Imperiali for help with interpreting the mass spectrometry data; C. Eickmann for help with AlphaFold2 predictions; the MIT BioMicroCenter and its staff for their support with sequencing; the MIT Biopolymers and Proteomics Core and its staff for assisting in HPLC and mass spectrometry experiments; and S.

Imperiali帮助解释质谱数据；C、艾克曼（Eickmann）帮助进行AlphaFold2预测；麻省理工学院生物微中心及其工作人员对测序的支持；麻省理工学院生物聚合物和蛋白质组学核心及其工作人员协助HPLC和质谱实验；和S。

Srikant for help with T4 reverse genetics. M.T.L. is an Investigator of the Howard Hughes Medical Institute. This work was also supported by a Howard Hughes Medical Institute Gilliam Fellowship awarded to C.R.D. and a National Institutes of Health NIGMS grant 5F32 GM139231-02 to C.N.V.Author informationAuthor notesThese authors contributed equally: Christopher N.

Srikant寻求T4反向遗传学的帮助。M、 T.L.是霍华德·休斯医学研究所的研究员。这项工作也得到了霍华德·休斯医学研究所吉利姆奖学金（授予C.R.D.）和美国国立卫生研究院（National Institutes of Health NIGMS）授予C.N.V的5F32 GM139231-02的支持。作者信息作者注意到，这些作者做出了同样的贡献：克里斯托弗·N。

Vassallo, Christopher R. DoeringAuthors and AffiliationsDepartment of Biology, Massachusetts Institute of Technology, Cambridge, MA, USAChristopher N. Vassallo, Christopher R. Doering & Michael T. LaubHoward Hughes Medical Institute, Cambridge, MA, USAMichael T. LaubAuthorsChristopher N. VassalloView author publicationsYou can also search for this author in.

Vassallo，Christopher R.Doering作者和附属机构美国马萨诸塞州剑桥市麻省理工学院生物学系Christopher N.Vassallo，Christopher R.Doering＆Michael T.LaubHoward Hughes医学研究所，马萨诸塞州剑桥市，美国Michael T.LaubAuthorsChristopher N.VassalloView作者出版物您也可以在中搜索这位作者。

PubMed Google ScholarChristopher R. DoeringView author publicationsYou can also search for this author in

PubMed Google ScholarMichael T. LaubView author publicationsYou can also search for this author in

PubMed Google Scholarmamichael T.LaubView作者出版物您也可以在

PubMed Google ScholarContributionsC.R.D. and C.N.V. cultured bacteria and phages, created plasmids and strains, and conducted bacterial growth and phage plating assays. C.R.D. and C.N.V. performed RNA extractions and immuno-northern blots. RNA-seq, RIP–seq and all RNA-seq library preparation was performed by C.R.D.

。R、 D.和C.N.V.培养细菌和噬菌体，产生质粒和菌株，并进行细菌生长和噬菌体平板测定。C、 R.D.和C.N.V.进行了RNA提取和免疫northern印迹。RNA-seq，RIP-seq和所有RNA-seq文库制备均由C.R.D.进行。

In vitro ADPr RNA-seq was performed by C.N.V. IP–MS was performed by C.R.D. In vitro transcription and translation, protein immunoblotting, and T4 genome engineering and evolution were performed by C.N.V. Radiolabel incorporation assays were performed by C.R.D. Protein purification, in vitro ADPr assays, HPLC and ESI-MS were conducted by C.N.V.

体外ADPr RNA-seq由C.N.V.进行。IP-MS由C.R.D.进行。体外转录和翻译，蛋白质免疫印迹，T4基因组工程和进化由C.N.V.进行。放射性标记掺入测定由C.R.D.进行。蛋白质纯化，体外ADPr测定，HPLC和ESI-MS由C.N.V.进行。

Bioinformatic analyses were performed by C.R.D. and C.N.V. Structural predictions were performed by C.R.D. C.R.D., C.N.V. and M.T.L. designed experiments, analysed data, prepared figures and wrote the manuscript.Corresponding authorCorrespondence to.

生物信息学分析由C.R.D.和C.N.V.进行。结构预测由C.R.D.C.R.D.，C.N.V.和M.T.L.设计实验，分析数据，准备数字并撰写手稿。对应作者对应。

Michael T. Laub.Ethics declarations

迈克尔·T·劳布。道德宣言

Competing interests

相互竞争的利益

The authors declare no competing interests.

作者声明没有利益冲突。

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Nature thanks the anonymous reviewers for their contribution to the peer review of this work. Peer reviewer reports are available.

《自然》杂志感谢匿名审稿人对这项工作的同行评审做出的贡献。同行评审报告可用。

Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Extended data figures and tablesExtended Data Fig. 1 Taxonomic distribution of cmdTAC and efficiency of plaquing for BASEL and T-even phages.(a) Presence or absence of CmdTAC homologs in bacterial genera with > 1000 sequenced genomes (see Methods).

Additional informationPublisher的注释Springer Nature在已发布的地图和机构隶属关系中的管辖权主张方面保持中立。扩展数据图和表扩展数据图1 cmdTAC的分类分布和巴塞尔和T-even噬菌体的噬菌体效率。（a）具有>1000个测序基因组的细菌属中是否存在CmdTAC同源物（请参见方法）。

(b) Examples of CmdTAC homologs found in diverse bacterial species. Grey bars between genes capture percent identity, defined by the color bar below. (c) Plaquing of the phages indicated on E. coli K12 harboring cmdTAC under control of its native promoter or an empty vector control. Data used to generate EOP data in Fig.

（b）在不同细菌物种中发现的CmdTAC同源物的例子。基因之间的灰色条捕获百分比同一性，由下面的颜色条定义。（c）在其天然启动子或空载体对照的控制下，在含有cmdTAC的大肠杆菌K12上显示的噬菌体的噬菌体。图中用于生成EOP数据的数据。

1c. (d) Plaquing of T4 phage on EV, cmdTAC+, or cmdT*AC+. (e) Survival assay of empty vector, cmdTAC+ cells or cells expressing a direct defense system (PD-T4-1) from its native promoter on the same low-copy plasmid. Values represent the number of CFUs of each strain after 18 min of infection divided by the CFUs pre-infection.

1c。（d）在EV，cmdTAC+或cmdT*AC+上放置T4噬菌体。（e）空载体，cmdTAC+细胞或在同一低拷贝质粒上从其天然启动子表达直接防御系统（PD-T4-1）的细胞的存活测定。数值表示感染18分钟后每个菌株的CFU数量除以CFU感染前。

Boxplots represent the median and quartile ranges of n = 4 biological replicates, with whiskers indicating max/min values. p-values are indicated at the top and represent a two-sided independent t-test. (f) Efficiency of center of infection assays with cmdTAC+ cells which measures the number of infected cells that go on to produce > 0 progeny phage.

箱形图表示n=4个生物学重复的中位数和四分位数范围，胡须表示最大/最小值。p值显示在顶部，代表双侧独立t检验。（f）用cmdTAC+细胞进行感染中心测定的效率，该细胞测量继续产生>0后代噬菌体的感染细胞的数量。

Value is measured relative to the empty vector control. Boxplots represent the median and quartile ranges of n = 4 biological replicates, with whiskers indicating max/min values.Source DataExtended Data Fig. 2 AlphaFold2-based prediction of CmdTAC structures.(a-c) AlphaFold2 predicted structures of CmdT (A), CmdA (B), and tetrameric CmdC (C).

相对于空向量控件测量值。箱形图表示n=4个生物学重复的中位数和四分位数范围，胡须表示最大/最小值。源数据扩展数据图2基于AlphaFold2的CmdTAC结构预测。（a-c）AlphaFold2预测CmdT（a），CmdA（B）和四聚体CmdC（c）的结构。

For the CmdC tetramer in panel (c) each subun.

对于面板（c）中的CmdC四聚体，每个子单元。

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Reprints and permissionsAbout this articleCite this articleVassallo, C.N., Doering, C.R. & Laub, M.T. Anti-viral defence by an mRNA ADP-ribosyltransferase that blocks translation.

转载和许可本文引用本文Vassallo，C.N.，Doering，C.R。＆Laub，M.T。通过阻断翻译的mRNA ADP-核糖基转移酶进行抗病毒防御。

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