Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
Cell Death Dis. 2023 Oct 23;14(10):695. doi: 10.1038/s41419-023-06222-z.
The selenium-containing enzyme GPX4 moonlights as a central regulator of ferroptosis, an iron-dependent, nonapoptotic form of regulated cell death caused by lipid peroxidation. Yet, little is known about the mechanisms underlying the regulation of its post-transcriptional modifications. Here, we identify the tripartite motif-containing protein TRIM26 as an E3 ubiquitin ligase of GPX4. TRIM26 directly interacts with GPX4 through its Ring domain and catalyzes the ubiquitination of GPX4 at K107 and K117, which promotes the switch in polyubiquitination of GPX4 from K48 to K63, thus enhancing GPX4 protein stability. Moreover, PLK1-mediated S127 phosphorylation of TRIM26 enhances the interaction between TRIM26 and GPX4. Inhibition of TRIM26 phosphorylation causes a reduction in GPX4 K63-linked polyubiquitination and diminishes GPX4 protein levels in tumor cells. Further investigation revealed that TRIM26 is overexpressed in glioma cells. TRIM26 silencing dramatically impedes ferroptosis resistance and tumorigenesis in glioma in vivo and in vitro. Clinically, TRIM26 expression shows a direct correlation with GPX4 and PLK1 levels in glioma samples and is associated with poor outcome in patients with glioma. Collectively, these findings define the role of GPX4 K63-linked polyubiquitination in ferroptosis and suggest a potential strategy for glioma treatment.
含硒酶 GPX4 兼职作为铁依赖性、非凋亡性细胞死亡形式的调控因子，这种细胞死亡形式由脂质过氧化引起。然而，关于其转录后修饰调控的机制知之甚少。在这里，我们鉴定出三结构域蛋白 TRIM26 是 GPX4 的 E3 泛素连接酶。TRIM26 通过其环结构域直接与 GPX4 相互作用，并催化 GPX4 在 K107 和 K117 上的泛素化，这促进了 GPX4 多泛素化从 K48 到 K63 的转变，从而增强了 GPX4 蛋白的稳定性。此外，PLK1 介导的 TRIM26 的 S127 磷酸化增强了 TRIM26 和 GPX4 之间的相互作用。抑制 TRIM26 的磷酸化会导致 GPX4 K63 连接的多泛素化减少，并降低肿瘤细胞中的 GPX4 蛋白水平。进一步的研究表明，TRIM26 在神经胶质瘤细胞中过表达。TRIM26 沉默在体内和体外显著阻碍了神经胶质瘤的铁死亡抵抗和肿瘤发生。临床上，TRIM26 的表达与神经胶质瘤样本中的 GPX4 和 PLK1 水平直接相关，并与神经胶质瘤患者的不良预后相关。总之，这些发现定义了 GPX4 K63 连接的多泛素化在铁死亡中的作用，并为神经胶质瘤的治疗提供了一种潜在的策略。
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