细致调控先天免疫对于机体有效应对入侵病原体是必要的。作为抗病毒免疫的重要组成部分，干扰素（IFN）调节因子3（IRF3）的稳定性和活性通过多种翻译后修饰紧密地受到控制。在本研究中，我们发现了一种含人卵巢肿瘤结构域的去泛素化酶OTUD6B，它作为IRF3的正调节因子促进了I型IFN先天抗病毒免疫信号。机制上，我们发现OTUD6B与IRF3相互作用并直接水解赖氨酸11（K11）和赖氨酸33（K33）连接的多泛素链，但只有IRF3的赖氨酸315位置的K33连接的多泛素对IRF3蛋白质酶解降解负有责任。值得注意的是，OTUD6B在体内增强了细胞的抗病毒反应，证明过表达人类OTUD6B的小鼠对RNA病毒感染更具抗性，且病毒载量和病情较轻。这些发现揭示了OTUD6B在调控先天性抗病毒免疫中的新作用，并为增强宿主抗病毒防御提供了潜在靶点。意义上，干扰素（IFN）调节因子（IRF3）是I型IFN转录的关键因子之一。为了精密地调控I型IFN抗病毒免疫应答，IRF3活性通过各种翻译后修饰紧密控制。然而，该调控机制尚未完全阐明。在本研究中，我们发现人类去泛素化酶OTUD6B正调节IRF3介导的抗病毒免疫应答。OTUD6B可以通过水解赖氨酸33连接的多泛素在Lys315处稳定IRF3蛋白质水平。更重要的是，OTUD6B过表达小鼠对RNA病毒感染表现出更高的抗性。因此，与先前的报道不同，表明斑马鱼OTUD6B通过抑制IRF3和IRF7的K63连接泛素化而负调节抗病毒应答，我们证明人类OTUD6B实际上增强了I型IFN应答，并具有抗病毒治疗的潜力。

Elaborate regulation of innate immunity is necessary for the host to effectively respond to invading pathogens. As an important component of antiviral immunity transcription factors, the stability and activity of interferon (IFN) regulatory factor 3 (IRF3) are tightly controlled via multiple post-translational modifications. Here, we identified a human ovarian tumor domain-containing deubiquitinase OTUD6B as a positive regulator of IRF3 that facilitates type I IFN innate antiviral immune signaling. Mechanically, we found that OTUD6B interacts with IRF3 and directly hydrolyzes both the lysine 11 (K11)- and the lysine 33 (K33)-linked polyubiquitin chain, but only K33-linked polyubiquitin at Lys315 of IRF3 is responsible for IRF3 proteasome degradation. Notably, OTUD6B enhanced cellular antiviral responses in vivo, as evidenced by mice that overexpressed human OTUD6B were more resistant to RNA virus infection and had reduced viral load and morbidity. These findings revealed a previously unknown role for OTUD6B in the regulation of innate antiviral immunity and may provide a potential target for enhancing host antiviral defense. IMPORTANCE 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.