UBL4A Augments Innate Immunity by Promoting the K63-Linked Ubiquitination of TRAF6
UBL4A Augments Innate Immunity by Promoting the K63-Linked Ubiquitination of TRAF6
复制标题
UBL4A 通过促进 TRAF6 的 K63 泛素化来增强先天免疫
DOI：
10.4049/jimmunol.1800750
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发表时间：
2019-10-01
影响因子：
4.4
通讯作者：
Zhang, Jun
中科院分区：
文献类型：
--
作者：
Peng, Shu-Jie;Yao, Ran-Ran;Zhang, Jun
UBL 4A是一个新的干扰素刺激基因。UBL 4A积极调节先天免疫应答。UBL 4A与TRAF 6相互作用并靶向K63连接的泛素化。在这项研究中显示，编码泛素样蛋白的人UBL 4A/GdX通过病毒感染和IFN刺激而上调。并对UBL 4A在抗病毒免疫应答中的作用进行了初步研究。UBL 4A的过表达促进RNA病毒诱导的ISRE或IFN-β或NF-κB活化，导致I型IFN转录增强和病毒复制减少。一致地，UBL 4A的敲低导致I型IFN转录减少和病毒复制增强。此外，UBL 4A的过表达促进了病毒诱导的TBK 1、IRF 3和IKKα/β的磷酸化。UBL 4A的敲低抑制了病毒诱导的TBK 1、IRF 3和IKKα/β的磷酸化。免疫共沉淀显示UBL 4A与TRAF 6相互作用，并且这种相互作用在病毒感染后增强。泛素化分析表明，UBL 4A促进TRAF 6的K63连接的泛素化。因此，我们揭示了UBL 4A通过增强TRAF 6的K63连接的泛素化在对抗病毒入侵的先天免疫应答中的新的正反馈调节。
Key Points UBL4A is a novel IFN-stimulated gene. UBL4A positively regulates innate immune response. UBL4A interacts with and targets TRAF6 for K63-linked ubiquitination. 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 UBL4A 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 UBL4A 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.