Department of Surgery, College of Medicine, Cancer Center, University of Illinois at Chicago, Chicago, IL 60612, USA.
Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.
Sci Signal. 2024 Apr 9;17(831):eadg7867. doi: 10.1126/scisignal.adg7867.
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 and . 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.
I 型干扰素 (IFNs) 对于抗病毒免疫反应至关重要，精细调节 I 型 IFN 的产生对于在不引起有害免疫病理学的情况下有效清除病毒至关重要。我们表明，转录因子 Miz1 通过将组蛋白去乙酰化酶 1 (HDAC1) 募集到 和 的启动子上来在小鼠肺上皮细胞中表观遗传地上调编码 I 型 IFNs 的基因的表达。Miz1 的功能丧失导致在甲型流感病毒 (IAV) 感染期间这些 I 型 IFNs 的产生增加，导致体外和体内病毒清除得到改善。IAV 感染通过促进 CUL4B（CUL4B）介导的泛素化和 E3 泛素连接酶 Mule（Mcl-1 泛素连接酶 E3；也称为 Huwe1 或 Arf-BP1）的降解，从而诱导 Miz1 的积累，Mule 是将 Miz1 靶向降解的 E3 泛素连接酶。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 在调节抗病毒防御中的一个先前未知的功能，以及流感病毒逃避宿主免疫防御的潜在机制。
