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
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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.

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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.
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