The ELF3-TRIM22-MAVS signaling axis regulates type I interferon and antiviral responses.

IF 4 2区 医学 Q2 VIROLOGY
Qiaozhi Zhao, Pan Pan, Lirong Mo, Jiangtao Wu, Shengjie Liao, Hua Lu, Qiwei Zhang, Xiaoshen Zhang
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引用次数: 0

Abstract

Activation of the innate immune response is essential for host cells to restrict the dissemination of invading viruses and other pathogens. Proteins belonging to the tripartite motif (TRIM) family are key effectors in antiviral innate immunity. Among these, TRIM22, a RING-type E3 ubiquitin ligase, has been recognized as a significant regulator in the pathogenesis of various diseases. In the present study, we identified TRIM22 as a critical modulator of mitochondrial antiviral signaling protein (MAVS) activation. Loss of TRIM22 function led to reduced production of type I interferons (IFNs) in response to viral infection such as influenza A virus (IAV) or vesicular stomatitis virus (VSV), thereby facilitating viral replication. Mechanistically, TRIM22 was found to enhance retinoic acid-inducible gene I (RIG-I)-mediated signaling through the catalysis of Lys63-linked polyubiquitination of MAVS, which, in turn, activated the TANK-binding kinase 1 (TBK1)/interferon regulatory factor 3 (IRF3) pathway, driving IFN-β production. Additionally, TRIM22 was shown to inhibit the assembly of the MAVS-NLRX1 inhibitory complex, further amplifying innate immune responses. Our findings also demonstrated that RNA virus infection upregulated TRIM22 expression via the nuclear translocation of ELF3, a transcription factor that activates TRIM22 gene expression. This regulatory loop underscores the role of TRIM22 in modulating the type I IFN pathway, providing critical insights into the host's antiviral defense mechanisms. Our research highlights the potential of targeting the ELF3-TRIM22-MAVS axis as a therapeutic strategy for enhancing antiviral immunity and preventing RNA virus infections.IMPORTANCEInterferon (IFN)-mediated antiviral responses are crucial for the host's defense against foreign pathogens and are regulated by various signaling pathways. The tripartite motif (TRIM) family, recognized for its multifaceted roles in immune regulation and antiviral defense, plays a significant part in this process. In our study, we explored the important role of TRIM22, a protein that helped regulate the host's immune response to viral infections. We found that TRIM22 enhances the Lys63-linked polyubiquitination of mitochondrial antiviral signaling protein (MAVS), which was essential for producing type I interferons. Interestingly, we discovered that the expression of TRIM22 increases after an RNA virus infection, due to a transcription factor ELF3, which moved into the nucleus of cells to activate TRIM22 transcription. This created a feedback loop that strengthens the role of TRIM22 in modulating the type I IFN pathway. By uncovering these mechanisms, we aimed to enhance our understanding of how the immune system works and provide insights that could lead to innovative antiviral therapies.

ELF3-TRIM22-MAVS信号轴调节I型干扰素和抗病毒反应。
激活先天免疫反应对宿主细胞限制入侵病毒和其他病原体的传播至关重要。tripartite motif (TRIM)家族蛋白是抗病毒先天免疫的关键效应因子。其中,TRIM22是一种ring型E3泛素连接酶,已被认为是多种疾病发病机制中的重要调节因子。在本研究中,我们发现TRIM22是线粒体抗病毒信号蛋白(MAVS)激活的关键调节剂。TRIM22功能的丧失导致I型干扰素(ifn)的产生减少,以应对病毒感染,如甲型流感病毒(IAV)或水疱性口炎病毒(VSV),从而促进病毒复制。机制上,TRIM22通过催化Lys63-linked MAVS的多泛素化,增强视黄酸诱导基因I (RIG-I)介导的信号传导,进而激活tank结合激酶1 (TBK1)/干扰素调节因子3 (IRF3)通路,驱动IFN-β的产生。此外,TRIM22被证明可以抑制MAVS-NLRX1抑制复合物的组装,进一步放大先天免疫反应。我们的研究结果还表明,RNA病毒感染通过激活TRIM22基因表达的转录因子ELF3的核易位上调TRIM22的表达。这一调控环强调了TRIM22在调节I型IFN通路中的作用,为了解宿主的抗病毒防御机制提供了重要的见解。我们的研究强调了靶向ELF3-TRIM22-MAVS轴作为增强抗病毒免疫和预防RNA病毒感染的治疗策略的潜力。干扰素(IFN)介导的抗病毒反应对宿主防御外来病原体至关重要,并受到多种信号通路的调节。tripartite motif (TRIM)家族在免疫调节和抗病毒防御中发挥着多方面的作用,在这一过程中起着重要作用。在我们的研究中,我们探索了TRIM22的重要作用,这是一种帮助调节宿主对病毒感染的免疫反应的蛋白质。我们发现TRIM22增强了线粒体抗病毒信号蛋白(MAVS)的lys63连锁多泛素化,这是产生I型干扰素所必需的。有趣的是,我们发现TRIM22的表达在RNA病毒感染后增加,这是由于转录因子ELF3进入细胞核激活TRIM22的转录。这创造了一个反馈回路,加强了TRIM22在调节I型IFN通路中的作用。通过揭示这些机制,我们旨在增强我们对免疫系统如何工作的理解,并提供可能导致创新抗病毒疗法的见解。
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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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