FBXW7是对DNA病毒的先天免疫反应的一个多方面调节因子。

IF 19.8 1区 医学 Q1 IMMUNOLOGY
Xue-Dan Sun, Jia-Li Wang, Xin-Yu Zhang, Zi-Lun Ruan, Wei Liang, Yi Guo, Wei-Tao Guan, Qing Yang, Ling Li, Hong-Bing Shu, Ming-Ming Hu
{"title":"FBXW7是对DNA病毒的先天免疫反应的一个多方面调节因子。","authors":"Xue-Dan Sun, Jia-Li Wang, Xin-Yu Zhang, Zi-Lun Ruan, Wei Liang, Yi Guo, Wei-Tao Guan, Qing Yang, Ling Li, Hong-Bing Shu, Ming-Ming Hu","doi":"10.1038/s41423-025-01336-0","DOIUrl":null,"url":null,"abstract":"<p><p>Upon DNA virus infection, cGAS senses viral DNA and triggers MITA (also called STING)-dependent induction of type I interferons (IFN-Is) and other cytokines/chemokines. IFN-Is further activate STAT1/2 to induce interferon-stimulated genes (ISGs) and the innate antiviral response. How the innate antiviral response is silenced in uninfected cells and efficiently mounts upon viral infection is not fully understood. In this study, we found that FBXW7, a substrate recognition component of the SCF E3 ubiquitin ligase complex, is a multifaceted regulator of the innate immune response to DNA viruses. In uninfected cells, FBXW7 mediates the polyubiquitination and degradation of GSK3α/β-phosphorylated SLC35B2/3 at the Golgi apparatus. This leads to the downregulation of sulfated glycosaminoglycans (sGAGs) in the Golgi apparatus and the inactivation of MITA in uninfected cells. In addition, FBXW7 mediates the degradation of GSK3α/β-phosphorylated MYC, which is a repressor of STAT1/2, leading to proper STAT1/2 levels in uninfected cells. The differential regulation of FBXW7 on MITA and STAT1/2 ensures inactivation but is ready for fast mount of the innate immune response in uninfected cells. Infection with DNA viruses activates the PI3K‒AKT axis, which inactivates GSK3α/β and inhibits FBXW7-mediated polyubiquitination and degradation of SLC35B2/3, leading to increased production of sGAGs, activation of MITA and rapid onset of the innate antiviral response. Consistently, gene disruption experiments indicate that FBXW7 modulates the innate antiviral response in human THP-1 and mouse BMDM cells. These findings suggest that FBXW7 functions as a versatile regulator of the innate immune response to DNA viruses by differentially regulating upstream and downstream components of the type I interferon induction loop.</p>","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":""},"PeriodicalIF":19.8000,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"FBXW7 is a multifaceted regulator of the innate immune response to DNA viruses.\",\"authors\":\"Xue-Dan Sun, Jia-Li Wang, Xin-Yu Zhang, Zi-Lun Ruan, Wei Liang, Yi Guo, Wei-Tao Guan, Qing Yang, Ling Li, Hong-Bing Shu, Ming-Ming Hu\",\"doi\":\"10.1038/s41423-025-01336-0\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Upon DNA virus infection, cGAS senses viral DNA and triggers MITA (also called STING)-dependent induction of type I interferons (IFN-Is) and other cytokines/chemokines. IFN-Is further activate STAT1/2 to induce interferon-stimulated genes (ISGs) and the innate antiviral response. How the innate antiviral response is silenced in uninfected cells and efficiently mounts upon viral infection is not fully understood. In this study, we found that FBXW7, a substrate recognition component of the SCF E3 ubiquitin ligase complex, is a multifaceted regulator of the innate immune response to DNA viruses. In uninfected cells, FBXW7 mediates the polyubiquitination and degradation of GSK3α/β-phosphorylated SLC35B2/3 at the Golgi apparatus. This leads to the downregulation of sulfated glycosaminoglycans (sGAGs) in the Golgi apparatus and the inactivation of MITA in uninfected cells. In addition, FBXW7 mediates the degradation of GSK3α/β-phosphorylated MYC, which is a repressor of STAT1/2, leading to proper STAT1/2 levels in uninfected cells. The differential regulation of FBXW7 on MITA and STAT1/2 ensures inactivation but is ready for fast mount of the innate immune response in uninfected cells. Infection with DNA viruses activates the PI3K‒AKT axis, which inactivates GSK3α/β and inhibits FBXW7-mediated polyubiquitination and degradation of SLC35B2/3, leading to increased production of sGAGs, activation of MITA and rapid onset of the innate antiviral response. Consistently, gene disruption experiments indicate that FBXW7 modulates the innate antiviral response in human THP-1 and mouse BMDM cells. These findings suggest that FBXW7 functions as a versatile regulator of the innate immune response to DNA viruses by differentially regulating upstream and downstream components of the type I interferon induction loop.</p>\",\"PeriodicalId\":9950,\"journal\":{\"name\":\"Cellular &Molecular Immunology\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":19.8000,\"publicationDate\":\"2025-09-08\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cellular &Molecular Immunology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1038/s41423-025-01336-0\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cellular &Molecular Immunology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41423-025-01336-0","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

在DNA病毒感染后,cGAS感知病毒DNA并触发MITA(也称为STING)依赖性诱导I型干扰素(IFN-Is)和其他细胞因子/趋化因子。IFN-Is进一步激活STAT1/2,诱导干扰素刺激基因(ISGs)和先天抗病毒反应。先天抗病毒反应如何在未感染细胞中沉默并有效地增加病毒感染尚不完全清楚。在这项研究中,我们发现FBXW7是SCF E3泛素连接酶复合物的一个底物识别成分,是DNA病毒先天免疫反应的一个多方面调节因子。在未感染的细胞中,FBXW7介导高尔基体中GSK3α/β-磷酸化SLC35B2/3的泛素化和降解。这导致高尔基体中硫酸糖胺聚糖(sGAGs)的下调和未感染细胞中MITA的失活。此外,FBXW7介导GSK3α/β-磷酸化MYC的降解,MYC是STAT1/2的抑制因子,导致未感染细胞中适当的STAT1/2水平。FBXW7对MITA和STAT1/2的差异调控确保了失活,但为未感染细胞的先天免疫应答的快速加载做好了准备。DNA病毒感染激活PI3K-AKT轴,使GSK3α/β失活,抑制fbxw7介导的多泛素化和SLC35B2/3的降解,导致sGAGs的产生增加,MITA的激活和先天抗病毒反应的快速发生。基因破坏实验一致表明,FBXW7调节人类THP-1和小鼠BMDM细胞的先天抗病毒反应。这些发现表明,FBXW7通过不同地调节I型干扰素诱导环的上游和下游组分,作为DNA病毒先天免疫反应的多功能调节剂。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
FBXW7 is a multifaceted regulator of the innate immune response to DNA viruses.

Upon DNA virus infection, cGAS senses viral DNA and triggers MITA (also called STING)-dependent induction of type I interferons (IFN-Is) and other cytokines/chemokines. IFN-Is further activate STAT1/2 to induce interferon-stimulated genes (ISGs) and the innate antiviral response. How the innate antiviral response is silenced in uninfected cells and efficiently mounts upon viral infection is not fully understood. In this study, we found that FBXW7, a substrate recognition component of the SCF E3 ubiquitin ligase complex, is a multifaceted regulator of the innate immune response to DNA viruses. In uninfected cells, FBXW7 mediates the polyubiquitination and degradation of GSK3α/β-phosphorylated SLC35B2/3 at the Golgi apparatus. This leads to the downregulation of sulfated glycosaminoglycans (sGAGs) in the Golgi apparatus and the inactivation of MITA in uninfected cells. In addition, FBXW7 mediates the degradation of GSK3α/β-phosphorylated MYC, which is a repressor of STAT1/2, leading to proper STAT1/2 levels in uninfected cells. The differential regulation of FBXW7 on MITA and STAT1/2 ensures inactivation but is ready for fast mount of the innate immune response in uninfected cells. Infection with DNA viruses activates the PI3K‒AKT axis, which inactivates GSK3α/β and inhibits FBXW7-mediated polyubiquitination and degradation of SLC35B2/3, leading to increased production of sGAGs, activation of MITA and rapid onset of the innate antiviral response. Consistently, gene disruption experiments indicate that FBXW7 modulates the innate antiviral response in human THP-1 and mouse BMDM cells. These findings suggest that FBXW7 functions as a versatile regulator of the innate immune response to DNA viruses by differentially regulating upstream and downstream components of the type I interferon induction loop.

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
CiteScore
31.20
自引率
1.20%
发文量
903
审稿时长
1 months
期刊介绍: Cellular & Molecular Immunology, a monthly journal from the Chinese Society of Immunology and the University of Science and Technology of China, serves as a comprehensive platform covering both basic immunology research and clinical applications. The journal publishes a variety of article types, including Articles, Review Articles, Mini Reviews, and Short Communications, focusing on diverse aspects of cellular and molecular immunology.
×
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