Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University , Suzhou, Jiangsu, China.
mBio. 2023 Oct 31;14(5):e0033223. doi: 10.1128/mbio.00332-23. Epub 2023 Aug 31.
Interferon (IFN) regulatory factor (IRF3) is one of the key factors for type I IFN transcription. To sophisticatedly regulate type I IFN antiviral immune response, IRF3 activity is closely controlled by a variety of post-translational modifications. However, the regulatory mechanisms are still not fully elucidated. In the present study, we found that human deubiquitinase OTUD6B positively regulates IRF3-mediated antiviral immune response. OTUD6B can stabilize the IRF3 protein level via hydrolyzing (Lys33)-linked polyubiquitin at Lys315. More importantly, mice with OTUD6B overexpression exhibited more resistance to RNA virus infection. Thus, unlike the previous report that zebrafish OTUD6B negatively regulates the antiviral response by suppressing K63-linked ubiquitination of IRF3 and IRF7, we demonstrate that human OTUD6B actually enhances type I IFN response and has the potential for antiviral therapy.
干扰素（IFN）调节因子（IRF3）是 I 型 IFN 转录的关键因素之一。为了精细调控 I 型 IFN 的抗病毒免疫反应，IRF3 的活性受到多种翻译后修饰的严格控制。然而，其调控机制仍未完全阐明。在本研究中，我们发现人源去泛素化酶 OTUD6B 通过水解 Lys315 上的（Lys33）连接多泛素来正向调控 IRF3 介导的抗病毒免疫反应。更重要的是，过表达 OTUD6B 的小鼠对 RNA 病毒感染的抵抗力更强。因此，与先前的报道相反，即斑马鱼 OTUD6B 通过抑制 IRF3 和 IRF7 的 K63 连接泛素化来负调控抗病毒反应，我们证明人源 OTUD6B 实际上增强了 I 型 IFN 反应，具有抗病毒治疗的潜力。
