E3连接酶ASB3通过靶向泛素-蛋白酶体降解MAVS来下调抗病毒先天免疫能力

IF 13.7 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Cell Death and Differentiation Pub Date : 2024-09-12 DOI:10.1038/s41418-024-01376-5
Mingyang Cheng, Yiyuan Lu, Jiarui Wang, Haixu Wang, Yu Sun, Wenhui Zhao, Junhong Wang, Chunwei Shi, Jiawei Luo, Ming Gao, Tianxin Yu, Jianzhong Wang, Jiayao Guan, Nan Wang, Wentao Yang, Yanlong Jiang, Haibin Huang, Guilian Yang, Xin Cao, Dongqin Yang, Chunfeng Wang, Yan Zeng
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引用次数: 0

摘要

E3 泛素连接酶在病毒感染期间对调节抗病毒免疫非常重要。在这里,我们发现在 RNA 病毒(尤其是甲型流感病毒(IAV))存在的情况下,E3 连接酶 Ankyrin repeat and SOCS box-containing protein 3 (ASB3) 会上调。值得注意的是,过表达 ASB3 会抑制仙台病毒(SeV)和 IAV 诱导的 I 型 IFN(IFN-I)反应,而消减 ASB3 则会恢复 SeV 和 H9N2 感染介导的 IFN-β 及其下游干扰素刺激基因(ISGs)的转录。有趣的是,缺乏 ASB3 的动物对 H9N2 和 H1N1 感染的易感性降低。从机理上讲,ASB3 与 MAVS 相互作用,直接介导 K48 链接的多泛素化和 MAVS 在 K297 处的降解,从而抑制 TBK1 和 IRF3 的磷酸化并下调下游抗病毒信号。这些发现确立了 ASB3 作为控制抗病毒信号激活的关键负调控因子的地位,并描述了 ASB3 以前未曾报道过的一种新功能。
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The E3 ligase ASB3 downregulates antiviral innate immunity by targeting MAVS for ubiquitin-proteasomal degradation

E3 ubiquitin ligases are very important for regulating antiviral immunity during viral infection. Here, we discovered that Ankyrin repeat and SOCS box-containing protein 3 (ASB3), an E3 ligase, are upregulated in the presence of RNA viruses, particularly influenza A virus (IAV). Notably, overexpression of ASB3 inhibits type I IFN (IFN-I) responses induced by Sendai virus (SeV) and IAV, and ablation of ASB3 restores SeV and H9N2 infection-mediated transcription of IFN-β and its downstream interferon-stimulated genes (ISGs). Interestingly, animals lacking ASB3 presented decreased susceptibility to H9N2 and H1N1 infections. Mechanistically, ASB3 interacts with MAVS and directly mediates K48-linked polyubiquitination and degradation of MAVS at K297, thereby inhibiting the phosphorylation of TBK1 and IRF3 and downregulating downstream antiviral signaling. These findings establish ASB3 as a critical negative regulator that controls the activation of antiviral signaling and describe a novel function of ASB3 that has not been previously reported.

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来源期刊
Cell Death and Differentiation
Cell Death and Differentiation 生物-生化与分子生物学
CiteScore
24.70
自引率
1.60%
发文量
181
审稿时长
3 months
期刊介绍: Mission, vision and values of Cell Death & Differentiation: To devote itself to scientific excellence in the field of cell biology, molecular biology, and biochemistry of cell death and disease. To provide a unified forum for scientists and clinical researchers It is committed to the rapid publication of high quality original papers relating to these subjects, together with topical, usually solicited, reviews, meeting reports, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.
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