2. Academic Validation
  3. The E3 ligase TRIM26 suppresses ferroptosis through catalyzing K63-linked ubiquitination of GPX4 in glioma

The E3 ligase TRIM26 suppresses ferroptosis through catalyzing K63-linked ubiquitination of GPX4 in glioma

  • Cell Death Dis. 2023 Oct 23;14(10):695. doi: 10.1038/s41419-023-06222-z.
Zhangjie Wang # 1,  Yuan Xia # 2 3,  Yang Wang # 1,  Ruiqiu Zhu 4,  Hongbo Li 5,  Yu Liu 1,  Na Shen 6
Affiliations

Affiliations

  • 1 Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
  • 2 Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
  • 3 Department of Hematology, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, 225300, China.
  • 4 Department of Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China.
  • 5 Department of Gastrointestinal Surgery, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310000, China.
  • 6 Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China. shenna1226@stu.njmu.edu.cn.
  • # Contributed equally.
PMID: 37872147 DOI: 10.1038/s41419-023-06222-z
Abstract

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.

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