School of Life Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China; and.
Guangdong Provincial Key Laboratory of Liver Disease, Cell-Gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510630, China.
J Immunol. 2020 Mar 15;204(6):1499-1507. doi: 10.4049/jimmunol.1900482. Epub 2020 Feb 5.
As an important effector in response to various intracellular or extracellular stimuli, the NF-κB family extensively participates in a wide spectrum of biological events, and its dysregulation may result in many pathological conditions, such as microbial infection, tumor progression, and neurodegenerative disorders. Previous investigations showed that multiple types of ubiquitination play critical roles in the modulation of the NF-κB signaling pathway, yet the molecular mechanisms are still poorly understood. In the current study, we identified TRIM25, an E3 ubiquitin ligase, as a novel positive regulator in mediating NF-κB activation in human embryonic kidney 293T (HEK293T), HeLa cells, THP-1 cells, and PBMCs. The expression of TRIM25 promoted TNF-α-induced NF-κB signaling, whereas the knockdown had the opposite effect. Furthermore, TRIM25 interacted with TRAF2 and enhanced the K63-linked polyubiquitin chains attached to TRAF2. Moreover, TRIM25 bridged the interaction of TRAF2 and TAK1 or IKKβ. To our knowledge, our study has identified a previously unrecognized role for TRIM25 in the regulation of NF-κB activation by enhancing the K63-linked ubiquitination of TRAF2.
作为对各种细胞内或细胞外刺激的重要效应因子，NF-κB 家族广泛参与广泛的生物事件，其失调可能导致许多病理状况，如微生物感染、肿瘤进展和神经退行性疾病。先前的研究表明，多种类型的泛素化在调节 NF-κB 信号通路中发挥着关键作用，但分子机制仍知之甚少。在本研究中，我们鉴定了 E3 泛素连接酶 TRIM25，作为一种新型的正调节剂，介导人胚肾 293T（HEK293T）、HeLa 细胞、THP-1 细胞和 PBMC 中 NF-κB 的激活。TRIM25 的表达促进了 TNF-α 诱导的 NF-κB 信号转导，而敲低则有相反的效果。此外，TRIM25 与 TRAF2 相互作用，并增强 TRAF2 上的 K63 连接多泛素链。此外，TRIM25 桥接 TRAF2 和 TAK1 或 IKKβ 的相互作用。据我们所知，我们的研究首次发现 TRIM25 通过增强 TRAF2 的 K63 连接泛素化来调节 NF-κB 的激活，从而在 NF-κB 激活的调节中发挥了以前未被认识的作用。
