State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400715, China.
Cancer Center, Medical Research Institute, Southwest University, Chongqing 400715, China.
Int J Mol Sci. 2022 Sep 5;23(17):10161. doi: 10.3390/ijms231710161.
The process of ubiquitination regulates the degradation, transport, interaction, and stabilization of substrate proteins, and is crucial for cell signal transduction and function. TNF receptor-associated factor 4, TRAF4, is a member of the TRAF family and is involved in the process of ubiquitination as an E3 ubiquitin protein ligase. Here, we found that TRAF4 expression correlates with glioma subtype and grade, and that TRAF4 is significantly overexpressed in glioblastoma and predicts poor prognosis. Knockdown of TRAF4 significantly inhibited the growth, proliferation, migration, and invasion of glioblastoma cells. Mechanistically, we found that TRAF4 only interacts with the Tudor domain of the AKT pathway activator SETDB1. TRAF4 mediates the atypical ubiquitination of SETDB1 to maintain its stability and function, thereby promoting the activation of the AKT pathway. Restoring SETDB1 expression in TRAF4 knockdown glioblastoma cells partially restored cell growth and proliferation. Collectively, our findings reveal a novel mechanism by which TRAF4 mediates AKT pathway activation, suggesting that TRAF4 may serve as a biomarker and promising therapeutic target for glioblastoma.
泛素化过程调节底物蛋白的降解、转运、相互作用和稳定，对于细胞信号转导和功能至关重要。TNF 受体相关因子 4（TRAF4）是 TRAF 家族的一员，作为 E3 泛素蛋白连接酶参与泛素化过程。在这里，我们发现 TRAF4 的表达与神经胶质瘤亚型和分级相关，并且在胶质母细胞瘤中显著过表达，并且预测预后不良。TRAF4 的敲低显著抑制胶质母细胞瘤细胞的生长、增殖、迁移和侵袭。在机制上，我们发现 TRAF4 仅与 AKT 通路激活剂 SETDB1 的 Tudor 结构域相互作用。TRAF4 介导 SETDB1 的非典型泛素化以维持其稳定性和功能，从而促进 AKT 通路的激活。在 TRAF4 敲低的胶质母细胞瘤细胞中恢复 SETDB1 的表达部分恢复了细胞的生长和增殖。总之，我们的研究结果揭示了 TRAF4 介导 AKT 通路激活的新机制，表明 TRAF4 可能作为胶质母细胞瘤的生物标志物和有前途的治疗靶点。
