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.

中文翻译：

---

Miz1 抑制 I 型干扰素产生并限制甲型流感病毒感染期间的病毒清除

I 型干扰素 (IFN) 对于抗病毒免疫反应至关重要，而微调 I 型干扰素的产生对于有效清除病毒而不引起有害的免疫病理学至关重要。我们发现，转录因子 Miz1 通过将组蛋白脱乙酰酶 1 (HDAC1) 募集至 I 型干扰素的启动子，从而在表观遗传上抑制小鼠肺上皮细胞中编码 I 型干扰素的基因的表达。伊夫纳和干扰素。 Miz1 功能的丧失导致甲型流感病毒 (IAV) 感染期间这些 I 型干扰素的产生增加，从而改善体外和体内的病毒清除率。 IAV 感染通过促进 cullin-4B (CUL4B) 介导的 E3 泛素连接酶 Mule（Mcl-1 泛素连接酶 E3；也称为 Huwe1 或 Arf-BP1）的泛素化和降解来诱导 Miz1 积累，该酶以 Miz1 为目标进行降解。因此，Miz1 的积累限制了 I 型 IFN 的产生并有利于病毒复制。这项研究揭示了 Miz1 在调节抗病毒防御方面先前未被认识的功能以及流感病毒逃避宿主免疫防御的潜在机制。