Department of Veterinary Medicine & Institute of Preventive Veterinary Sciences, Zhejiang University College of Animal Sciences, Hangzhou, Zhejiang, China.
Hainan Institute of Zhejiang University, Sanya, Hainan, China.
PLoS Pathog. 2023 Jul 27;19(7):e1011550. doi: 10.1371/journal.ppat.1011550. eCollection 2023 Jul.
Influenza A virus (IAV) expresses several accessory proteins to limit host anti-viral restriction factors to facilitate viral replication. The Ten-Eleven Translocation 2 (TET2) is a methylcytosine dioxygenase that promotes DNA demethylation by catalyzing the oxidation of 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), which plays a vital role in hematopoiesis and immunity. Here we report that TET2 is a host restriction factor that limits IAV replication. But IAV endoribonuclease PA-X is able to remove the replication restriction by binding to TET2 mRNA and driving TET2 mRNA degradation to reduce TET2 expression during infection. Genetic inactivation of TET2 markedly enhances IAV replication in vitro and in vivo. Mechanistically, we found that TET2 regulates demethylation and transcription of STAT1 and some interferon-stimulated genes (ISGs), including ISG15, ISG20, and IFIT5, so the loss of TET2 greatly impairs type I Interferon signaling. Furthermore, we confirmed that TET2-mediated demethylation of the STAT1 gene is critical for interferon anti-viral activity. Our study demonstrates that the host TET2 is essential to the innate immune response against IAV infection.
甲型流感病毒（IAV）表达几种辅助蛋白，以限制宿主抗病毒限制因子，从而促进病毒复制。Ten-Eleven Translocation 2（TET2）是一种 5-甲基胞嘧啶双加氧酶，通过催化 5-甲基胞嘧啶（5mC）氧化为 5-羟甲基胞嘧啶（5hmC）来促进 DNA 去甲基化，在造血和免疫中发挥重要作用。在这里，我们报告 TET2 是一种宿主限制因子，限制 IAV 的复制。但 IAV 内切核糖核酸酶 PA-X 能够通过与 TET2 mRNA 结合并驱动 TET2 mRNA 降解，从而在感染过程中降低 TET2 表达，从而消除复制限制。TET2 的遗传失活显著增强了 IAV 在体外和体内的复制。在机制上，我们发现 TET2 调节 STAT1 和一些干扰素刺激基因（ISGs）的去甲基化和转录，包括 ISG15、ISG20 和 IFIT5，因此 TET2 的缺失极大地损害了 I 型干扰素信号。此外，我们证实 TET2 介导的 STAT1 基因去甲基化对于干扰素抗病毒活性至关重要。我们的研究表明，宿主 TET2 对于针对 IAV 感染的先天免疫反应至关重要。
