RNF20 dual regulation of MDA5 signaling to maintain immune homeostasis in chickens.

IF 4 2区 医学 Q2 VIROLOGY
Journal of Virology Pub Date : 2025-03-18 Epub Date: 2025-02-25 DOI:10.1128/jvi.02008-24
Jie Wang, Qiuju Liu, Kehui Zhang, Shurui Zhao, Qi Shao, Feiyu Fu, Jingjiao Ma, Zhaofei Wang, Ya-Xian Yan, Hengan Wang, Jianhe Sun, Yuqiang Cheng
{"title":"RNF20 dual regulation of MDA5 signaling to maintain immune homeostasis in chickens.","authors":"Jie Wang, Qiuju Liu, Kehui Zhang, Shurui Zhao, Qi Shao, Feiyu Fu, Jingjiao Ma, Zhaofei Wang, Ya-Xian Yan, Hengan Wang, Jianhe Sun, Yuqiang Cheng","doi":"10.1128/jvi.02008-24","DOIUrl":null,"url":null,"abstract":"<p><p>RIG-I and MDA5, known as the RIG-I-like receptors (RLRs), play a pivotal role in inducing antiviral responses to RNA viral infections. While chickens lack RIG-I, they possess a functionally enhanced MDA5 that recognizes pathogens and regulates immunity, underscoring the critical role of MDA5 in maintaining immune homeostasis in chickens. However, the precise mechanisms governing the expression and optimal activation of MDA5 remain unclear. Here, we reveal that the chicken E3 ubiquitin ligase RNF20 is essential for modulating MDA5-mediated innate immune homeostasis. Transcriptome sequencing analysis revealed that RNA viral infection of DF-1 cells significantly upregulated the expression of chicken RNF20. Overexpression of RNF20 markedly suppresses the expression of chicken innate immunity-related genes, while RNF20 knockout leads to immune deficiency both <i>in vivo</i> and <i>in vitro</i>. Mechanistically, RNF20 is located in the nucleus, where it maintains the basic expression and regulates the inducible expression of MDA5 to establish immune defense during the early infection phase. In the late phase, RNF20 translocates to the cytoplasm, where it facilitates the K27- and K48-linked polyubiquitination and subsequent degradation of MDA5, thereby preventing immune overstimulation. Overall, this study establishes RNF20 as an important E3 ubiquitin ligase that maintains chicken innate immune homeostasis.</p><p><strong>Importance: </strong>Chicken MDA5 is an important RNA viral sensor for initiating the antiviral innate immune response. The protein level of MDA5 must be tightly regulated to maintain antiviral innate immune homeostasis. In this study, we demonstrate that the E3 ubiquitin ligase RNF20 precisely regulates MDA5 protein stabilization through nucleoplasmic translocation. Specifically, in uninfected and during early infection, RNF20 regulates MDA5 transcription in the nucleus. While in the late stages of infection, RNF20 translocates out of the nucleus and catalyzes the ubiquitinated degradation of MDA5. Thus, RNF20 is important in regulating chicken antiviral innate immune homeostasis.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0200824"},"PeriodicalIF":4.0000,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915864/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Virology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1128/jvi.02008-24","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/2/25 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"VIROLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

RIG-I and MDA5, known as the RIG-I-like receptors (RLRs), play a pivotal role in inducing antiviral responses to RNA viral infections. While chickens lack RIG-I, they possess a functionally enhanced MDA5 that recognizes pathogens and regulates immunity, underscoring the critical role of MDA5 in maintaining immune homeostasis in chickens. However, the precise mechanisms governing the expression and optimal activation of MDA5 remain unclear. Here, we reveal that the chicken E3 ubiquitin ligase RNF20 is essential for modulating MDA5-mediated innate immune homeostasis. Transcriptome sequencing analysis revealed that RNA viral infection of DF-1 cells significantly upregulated the expression of chicken RNF20. Overexpression of RNF20 markedly suppresses the expression of chicken innate immunity-related genes, while RNF20 knockout leads to immune deficiency both in vivo and in vitro. Mechanistically, RNF20 is located in the nucleus, where it maintains the basic expression and regulates the inducible expression of MDA5 to establish immune defense during the early infection phase. In the late phase, RNF20 translocates to the cytoplasm, where it facilitates the K27- and K48-linked polyubiquitination and subsequent degradation of MDA5, thereby preventing immune overstimulation. Overall, this study establishes RNF20 as an important E3 ubiquitin ligase that maintains chicken innate immune homeostasis.

Importance: Chicken MDA5 is an important RNA viral sensor for initiating the antiviral innate immune response. The protein level of MDA5 must be tightly regulated to maintain antiviral innate immune homeostasis. In this study, we demonstrate that the E3 ubiquitin ligase RNF20 precisely regulates MDA5 protein stabilization through nucleoplasmic translocation. Specifically, in uninfected and during early infection, RNF20 regulates MDA5 transcription in the nucleus. While in the late stages of infection, RNF20 translocates out of the nucleus and catalyzes the ubiquitinated degradation of MDA5. Thus, RNF20 is important in regulating chicken antiviral innate immune homeostasis.

RNF20双调控MDA5信号维持鸡免疫稳态。
RIG-I和MDA5被称为RIG-I样受体(rlr),在诱导RNA病毒感染的抗病毒反应中起关键作用。虽然鸡缺乏rig - 1,但它们具有功能增强的MDA5,可以识别病原体并调节免疫,这强调了MDA5在维持鸡免疫稳态中的关键作用。然而,控制MDA5表达和最佳激活的确切机制尚不清楚。在这里,我们发现鸡E3泛素连接酶RNF20在调节mda5介导的先天免疫稳态中是必不可少的。转录组测序分析显示,RNA病毒感染DF-1细胞可显著上调鸡RNF20的表达。过表达RNF20可显著抑制鸡先天免疫相关基因的表达,而敲除RNF20可导致体内和体外免疫缺陷。机制上,RNF20位于细胞核内,维持基本表达,并在感染早期调控MDA5的诱导表达,建立免疫防御。在后期,RNF20转运到细胞质中,促进K27-和k48相关的多泛素化和随后的MDA5降解,从而防止免疫过度刺激。总之,本研究确定RNF20是维持鸡先天免疫稳态的重要E3泛素连接酶。重要性:鸡MDA5是启动抗病毒先天免疫反应的重要RNA病毒传感器。必须严格调节MDA5蛋白水平以维持抗病毒先天免疫稳态。在这项研究中,我们证明了E3泛素连接酶RNF20通过核质易位精确调节MDA5蛋白的稳定性。具体来说,在未感染和早期感染中,RNF20调节细胞核中MDA5的转录。而在感染后期,RNF20转出细胞核并催化MDA5的泛素化降解。因此,RNF20在调节鸡抗病毒先天免疫稳态中起重要作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Journal of Virology
Journal of Virology 医学-病毒学
CiteScore
10.10
自引率
7.40%
发文量
906
审稿时长
1 months
期刊介绍: Journal of Virology (JVI) explores the nature of the viruses of animals, archaea, bacteria, fungi, plants, and protozoa. We welcome papers on virion structure and assembly, viral genome replication and regulation of gene expression, genetic diversity and evolution, virus-cell interactions, cellular responses to infection, transformation and oncogenesis, gene delivery, viral pathogenesis and immunity, and vaccines and antiviral agents.
×
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:481959085
Book学术官方微信