Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Ministry of Health (Peking University), Peking University Health Science Center, Beijing 100191, China.
Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Ministry of Health (Peking University), Peking University Health Science Center, Beijing 100191, China
J Immunol. 2019 Oct 1;203(7):1943-1951. doi: 10.4049/jimmunol.1800750. Epub 2019 Aug 26.
Human UBL4A/GdX, encoding an ubiquitin-like protein, was shown in this study to be upregulated by viral infection and IFN stimulation. Then the functions of UBL4A in antiviral immune response were characterized. Overexpression of UBL4A promoted RNA virus-induced ISRE or IFN-β or NF-κB activation, leading to enhanced type I IFN transcription and reduced virus replication. Consistently, knockdown of resulted in reduced type I IFN transcription and enhanced virus replication. Additionally, overexpression of UBL4A promoted virus-induced phosphorylation of TBK1, IRF3, and IKKα/β. Knockdown of inhibited virus-induced phosphorylation of TBK1, IRF3, and IKKα/β. Coimmunoprecipitation showed that UBL4A interacted with TRAF6, and this interaction was enhanced upon viral infection. Ubiquitination assays showed that UBL4A promoted the K63-linked ubiquitination of TRAF6. Therefore, we reveal a novel positive feedback regulation of UBL4A in innate immune response combating virus invasion by enhancing the K63-linked ubiquitination of TRAF6.
在这项研究中，人 UBL4A/GdX，编码一种泛素样蛋白，被证明在病毒感染和 IFN 刺激下上调。然后，研究了 UBL4A 在抗病毒免疫反应中的功能。UBL4A 的过表达促进了 RNA 病毒诱导的 ISRE 或 IFN-β 或 NF-κB 激活，导致 I 型 IFN 转录增强和病毒复制减少。一致地， 的敲低导致 I 型 IFN 转录减少和病毒复制增强。此外，UBL4A 的过表达促进了病毒诱导的 TBK1、IRF3 和 IKKα/β 的磷酸化。 的敲低抑制了病毒诱导的 TBK1、IRF3 和 IKKα/β 的磷酸化。免疫共沉淀显示 UBL4A 与 TRAF6 相互作用，而这种相互作用在病毒感染后增强。泛素化实验表明 UBL4A 促进了 TRAF6 的 K63 连接泛素化。因此，我们揭示了 UBL4A 在先天免疫反应中通过增强 TRAF6 的 K63 连接泛素化来对抗病毒入侵的一种新的正反馈调节机制。
