Miz1 在甲型流感病毒感染过程中抑制 I 型干扰素的产生并限制病毒的清除

IF 6.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling Pub Date : 2024-04-09 DOI:10.1126/scisignal.adg7867

Wenjiao Wu, Vinothini Arunagiri, Hanh Chi Do-Umehara, Cong Chen, Shuyin Gu, Indrani Biswas, Karen M. Ridge, G. R. Scott Budinger, Shuwen Liu, Jing Liu

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引用次数: 0

摘要

I型干扰素（IFN）是抗病毒免疫反应的关键，而微调I型干扰素的产生对有效清除病毒而不引起有害的免疫病理至关重要。我们发现，转录因子Miz1通过招募组蛋白去乙酰化酶1（HDAC1）到Ifna和Ifnb的启动子上，对小鼠肺上皮细胞中编码I型IFN的基因的表达进行表观遗传学抑制。在甲型流感病毒（IAV）感染期间，Miz1的功能缺失会导致这些I型IFNs的产生增加，从而提高体外和体内的病毒清除率。IAV 感染通过促进 Cullin-4B (CUL4B) 介导的泛素化和 E3 泛素连接酶 Mule（Mcl-1 泛素连接酶 E3；又称 Huwe1 或 Arf-BP1）的降解来诱导 Miz1 的积累，而 Mule 是 Miz1 的降解靶标。因此，Miz1 的积累限制了 I 型 IFN 的产生，有利于病毒的复制。这项研究揭示了 Miz1 在调节抗病毒防御中一种以前未被发现的功能，以及流感病毒逃避宿主免疫防御的一种潜在机制。

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Miz1 represses type I interferon production and limits viral clearance during influenza A virus infection

Type I interferons (IFNs) are critical for the antiviral immune response, and fine-tuning type I IFN production is critical to effectively clearing viruses without causing harmful immunopathology. We showed that the transcription factor Miz1 epigenetically repressed the expression of genes encoding type I IFNs in mouse lung epithelial cells by recruiting histone deacetylase 1 (HDAC1) to the promoters of Ifna and Ifnb. Loss of function of Miz1 resulted in augmented production of these type I IFNs during influenza A virus (IAV) infection, leading to improved viral clearance in vitro and in vivo. IAV infection induced Miz1 accumulation by promoting the cullin-4B (CUL4B)–mediated ubiquitylation and degradation of the E3 ubiquitin ligase Mule (Mcl-1 ubiquitin ligase E3; also known as Huwe1 or Arf-BP1), which targets Miz1 for degradation. As a result, Miz1 accumulation limited type I IFN production and favored viral replication. This study reveals a previously unrecognized function of Miz1 in regulating antiviral defense and a potential mechanism for influenza viruses to evade host immune defense.

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来源期刊

Science Signaling BIOCHEMISTRY & MOLECULAR BIOLOGY-CELL BIOLOGY

CiteScore

9.50

自引率

0.00%

发文量

148

审稿时长

3-8 weeks

期刊介绍： "Science Signaling" is a reputable, peer-reviewed journal dedicated to the exploration of cell communication mechanisms, offering a comprehensive view of the intricate processes that govern cellular regulation. This journal, published weekly online by the American Association for the Advancement of Science (AAAS), is a go-to resource for the latest research in cell signaling and its various facets. The journal's scope encompasses a broad range of topics, including the study of signaling networks, synthetic biology, systems biology, and the application of these findings in drug discovery. It also delves into the computational and modeling aspects of regulatory pathways, providing insights into how cells communicate and respond to their environment. In addition to publishing full-length articles that report on groundbreaking research, "Science Signaling" also features reviews that synthesize current knowledge in the field, focus articles that highlight specific areas of interest, and editor-written highlights that draw attention to particularly significant studies. This mix of content ensures that the journal serves as a valuable resource for both researchers and professionals looking to stay abreast of the latest advancements in cell communication science.