甲病毒复制酶成分nsP3的邻近相互作用组包括原宿主因子eIF4G和AHNAK。

IF 5.5 1区 医学 Q1 MICROBIOLOGY
PLoS Pathogens Pub Date : 2025-04-07 eCollection Date: 2025-04-01 DOI:10.1371/journal.ppat.1013050
Aditya Thiruvaiyaru, Sari Mattila, Mohammadreza Sadeghi, Krystyna Naumenko, Andres Merits, Markku Varjosalo, Tero Ahola
{"title":"甲病毒复制酶成分nsP3的邻近相互作用组包括原宿主因子eIF4G和AHNAK。","authors":"Aditya Thiruvaiyaru, Sari Mattila, Mohammadreza Sadeghi, Krystyna Naumenko, Andres Merits, Markku Varjosalo, Tero Ahola","doi":"10.1371/journal.ppat.1013050","DOIUrl":null,"url":null,"abstract":"<p><p>All positive-strand RNA viruses replicate their genomes in association with modified intracellular membranes, inducing either membrane invaginations termed spherules, or double-membrane vesicles. Alphaviruses encode four non-structural proteins nsP1-nsP4, all of which are essential for RNA replication and spherule formation. To understand the host factors associated with the replication complex, we fused the efficient biotin ligase miniTurbo with Semliki Forest virus (SFV) nsP3, which is located on the cytoplasmic surface of the spherules. We characterized the proximal proteome of nsP3 in three cell lines, including cells unable to form stress granules, and identified >300 host proteins constituting the microenvironment of nsP3. These included all the nsPs, as well as several previously characterized nsP3 binding proteins. However, the majority of the identified interactors had no previously identified roles in alphavirus replication, including 39 of the top 50 interacting proteins. The most prominent biological processes involving the proximal proteins were nucleic acid metabolism, translational regulation, cytoskeletal rearrangement and membrane remodeling. siRNA silencing confirmed six novel proviral factors, USP10, AHNAK, eIF4G1, SH3GL1, XAB2 and ANKRD17, which are associated with distinct cellular functions. All of these except SH3GL1 were also important for the replication of chikungunya virus. We discovered that the small molecule 4E1RCat, which inhibits the interaction between the canonical translation initiation factors eIF4G and eIF4E, exhibits antiviral activity against SFV. Since the same molecule was previously found to inhibit coronaviruses, this suggest the possibility that translation initiation factors could be considered as targets for broadly acting antivirals.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 4","pages":"e1013050"},"PeriodicalIF":5.5000,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12005498/pdf/","citationCount":"0","resultStr":"{\"title\":\"Proximity interactome of alphavirus replicase component nsP3 includes proviral host factors eIF4G and AHNAK.\",\"authors\":\"Aditya Thiruvaiyaru, Sari Mattila, Mohammadreza Sadeghi, Krystyna Naumenko, Andres Merits, Markku Varjosalo, Tero Ahola\",\"doi\":\"10.1371/journal.ppat.1013050\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>All positive-strand RNA viruses replicate their genomes in association with modified intracellular membranes, inducing either membrane invaginations termed spherules, or double-membrane vesicles. Alphaviruses encode four non-structural proteins nsP1-nsP4, all of which are essential for RNA replication and spherule formation. To understand the host factors associated with the replication complex, we fused the efficient biotin ligase miniTurbo with Semliki Forest virus (SFV) nsP3, which is located on the cytoplasmic surface of the spherules. We characterized the proximal proteome of nsP3 in three cell lines, including cells unable to form stress granules, and identified >300 host proteins constituting the microenvironment of nsP3. These included all the nsPs, as well as several previously characterized nsP3 binding proteins. However, the majority of the identified interactors had no previously identified roles in alphavirus replication, including 39 of the top 50 interacting proteins. The most prominent biological processes involving the proximal proteins were nucleic acid metabolism, translational regulation, cytoskeletal rearrangement and membrane remodeling. siRNA silencing confirmed six novel proviral factors, USP10, AHNAK, eIF4G1, SH3GL1, XAB2 and ANKRD17, which are associated with distinct cellular functions. All of these except SH3GL1 were also important for the replication of chikungunya virus. We discovered that the small molecule 4E1RCat, which inhibits the interaction between the canonical translation initiation factors eIF4G and eIF4E, exhibits antiviral activity against SFV. Since the same molecule was previously found to inhibit coronaviruses, this suggest the possibility that translation initiation factors could be considered as targets for broadly acting antivirals.</p>\",\"PeriodicalId\":48999,\"journal\":{\"name\":\"PLoS Pathogens\",\"volume\":\"21 4\",\"pages\":\"e1013050\"},\"PeriodicalIF\":5.5000,\"publicationDate\":\"2025-04-07\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12005498/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"PLoS Pathogens\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1371/journal.ppat.1013050\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/4/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"MICROBIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"PLoS Pathogens","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1371/journal.ppat.1013050","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/4/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"MICROBIOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

所有正链RNA病毒复制其基因组与修饰的细胞膜相关,诱导称为小球体的膜内陷或双膜囊泡。甲病毒编码四种非结构蛋白nsP1-nsP4,它们都是RNA复制和球粒形成所必需的。为了了解与复制复合体相关的宿主因子,我们将高效生物素连接酶miniTurbo与位于小球体细胞质表面的塞姆利基森林病毒(SFV) nsP3融合。我们在三种细胞系(包括不能形成应激颗粒的细胞)中鉴定了nsP3的近端蛋白质组,并鉴定了构成nsP3微环境的bbb300宿主蛋白。这些包括所有的nsp,以及几个先前表征的nsP3结合蛋白。然而,大多数确定的相互作用蛋白在甲病毒复制中没有先前确定的作用,包括前50个相互作用蛋白中的39个。涉及近端蛋白的最突出的生物学过程是核酸代谢、翻译调节、细胞骨架重排和膜重塑。siRNA沉默证实了6个新的原体因子USP10、AHNAK、eIF4G1、SH3GL1、XAB2和ANKRD17,它们与不同的细胞功能相关。除SH3GL1外,所有这些基因对基孔肯雅病毒的复制也很重要。我们发现小分子4E1RCat抑制经典翻译起始因子eIF4G和eIF4E之间的相互作用,对SFV表现出抗病毒活性。由于之前发现了同样的分子可以抑制冠状病毒,这表明翻译起始因子可能被视为广谱抗病毒药物的靶标。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Proximity interactome of alphavirus replicase component nsP3 includes proviral host factors eIF4G and AHNAK.

All positive-strand RNA viruses replicate their genomes in association with modified intracellular membranes, inducing either membrane invaginations termed spherules, or double-membrane vesicles. Alphaviruses encode four non-structural proteins nsP1-nsP4, all of which are essential for RNA replication and spherule formation. To understand the host factors associated with the replication complex, we fused the efficient biotin ligase miniTurbo with Semliki Forest virus (SFV) nsP3, which is located on the cytoplasmic surface of the spherules. We characterized the proximal proteome of nsP3 in three cell lines, including cells unable to form stress granules, and identified >300 host proteins constituting the microenvironment of nsP3. These included all the nsPs, as well as several previously characterized nsP3 binding proteins. However, the majority of the identified interactors had no previously identified roles in alphavirus replication, including 39 of the top 50 interacting proteins. The most prominent biological processes involving the proximal proteins were nucleic acid metabolism, translational regulation, cytoskeletal rearrangement and membrane remodeling. siRNA silencing confirmed six novel proviral factors, USP10, AHNAK, eIF4G1, SH3GL1, XAB2 and ANKRD17, which are associated with distinct cellular functions. All of these except SH3GL1 were also important for the replication of chikungunya virus. We discovered that the small molecule 4E1RCat, which inhibits the interaction between the canonical translation initiation factors eIF4G and eIF4E, exhibits antiviral activity against SFV. Since the same molecule was previously found to inhibit coronaviruses, this suggest the possibility that translation initiation factors could be considered as targets for broadly acting antivirals.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
PLoS Pathogens
PLoS Pathogens MICROBIOLOGY-PARASITOLOGY
自引率
3.00%
发文量
598
期刊介绍: Bacteria, fungi, parasites, prions and viruses cause a plethora of diseases that have important medical, agricultural, and economic consequences. Moreover, the study of microbes continues to provide novel insights into such fundamental processes as the molecular basis of cellular and organismal function.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信