Department of Cell Biology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Laboratory of Epigenetics in Development and Tumorigenesis, Tianjin Research Center of Basic Medical Sciences, Tianjin Key Laboratory of Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease, Ministry of Education, Tianjin Medical University, Heping District, Tianjin 300070, People's Republic of China.
Department of Immunology, Beijing Key Laboratory for Cancer Invasion and Metastasis, Advanced Innovation Center for Human Brain Protection, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, People's Republic of China.
J Immunol. 2019 May 15;202(10):2957-2970. doi: 10.4049/jimmunol.1800656. Epub 2019 Apr 5.
MAVS is a critical adaptor required for activating an innate antiviral immune response against viral infection. The activation of MAVS requires modification of the Lys63-linked ubiquitination and formation of prion-like aggregates. However, the molecular mechanisms regulating MAVS activity remain largely obscured. In this study, we identified a deubiquitinase YOD1, also known as a member of the ovarian tumor family, as a negative regulator of MAVS activation in both human and murine cells. YOD1 was recruited to mitochondria to interact with MAVS through its UBX and Znf domains after viral infection. Subsequently, YOD1 cleaved the K63-linked ubiquitination and abrogated the formation of prion-like aggregates of MAVS, which led to attenuation of IRF3, P65 activation, and IFN-β production. Knockdown of YOD1 potentiated IRF3 and P65 activation, IFN-β production, and antiviral innate immune response to RNA virus. Our findings thus provided, to our knowledge, novel insights into the regulatory cascade of the cellular antiviral response through YOD1-mediated K63-linked deubiquitination and aggregation of MAVS.
MAVS 是一种关键的衔接蛋白，对于激活针对病毒感染的先天抗病毒免疫反应至关重要。MAVS 的激活需要 Lys63 连接的泛素化修饰和形成类朊病毒聚集。然而，调节 MAVS 活性的分子机制在很大程度上仍不清楚。在这项研究中，我们鉴定了一种去泛素化酶 YOD1，也称为卵巢肿瘤家族的成员，作为人源和鼠源细胞中 MAVS 激活的负调控因子。YOD1 在病毒感染后被招募到线粒体，通过其 UBX 和 Znf 结构域与 MAVS 相互作用。随后，YOD1 切割 K63 连接的泛素化并消除 MAVS 的类朊病毒聚集，导致 IRF3、P65 激活和 IFN-β 产生减少。YOD1 的敲低增强了 IRF3 和 P65 的激活、IFN-β 的产生和 RNA 病毒的抗病毒先天免疫反应。因此，我们的研究结果提供了，据我们所知，通过 YOD1 介导的 MAVS 的 K63 连接去泛素化和聚集的细胞抗病毒反应的调控级联的新见解。
