2. Academic Validation
  3. STUB1-mediated ubiquitination and degradation of NSUN2 promotes hepatocyte ferroptosis by decreasing m5C methylation of Gpx4 mRNA

STUB1-mediated ubiquitination and degradation of NSUN2 promotes hepatocyte ferroptosis by decreasing m5C methylation of Gpx4 mRNA

  • Cell Rep. 2024 Oct 24;43(11):114885. doi: 10.1016/j.celrep.2024.114885.
Xiaotian Zhang 1,  Yihua Zhang 2,  Rongrong Li 3,  Yibo Li 3,  Qi Wang 4,  Ying Wang 2,  Xinying Chen 3,  Weihua Wang 3,  Erli Pang 4,  Yanyan Li 5,  Jia Wang 6,  Jinping Zheng 5,  Junjie Zhang 7
Affiliations

Affiliations

  • 1 The Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Department of Biology, College of Life Sciences, Beijing Normal University, Beijing 100875, China. Electronic address: xiaotianzhang@bnu.edu.cn.
  • 2 Department of Biochemistry and Molecular Biology, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
  • 3 The Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Department of Biology, College of Life Sciences, Beijing Normal University, Beijing 100875, China.
  • 4 MOE Key Laboratory for Biodiversity Science and Ecological Engineering and Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China.
  • 5 Center for Healthy Aging, Changzhi Medical College, Changzhi 046000, China.
  • 6 Department of Immunology, Changzhi Medical College, Changzhi 046000, China.
  • 7 The Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Department of Biology, College of Life Sciences, Beijing Normal University, Beijing 100875, China. Electronic address: jjzhang@bnu.edu.cn.
PMID: 39453812 DOI: 10.1016/j.celrep.2024.114885
Abstract

Ferroptosis is an iron-dependent cell death that occurs due to the peroxidation of Phospholipids in the cell membrane. In this study, we find that the protein level of NSUN2 is significantly decreased in hepatocyte Ferroptosis. This is attributed to STUB1-mediated ubiquitination of NSUN2 at lysines 457 and 654, promoting NSUN2 degradation in Ferroptosis. Selenoprotein Glutathione Peroxidase 4 (GPX4) is a prominent suppressor of Ferroptosis. We find that downregulation of NSUN2 diminishes m5C methylation of Gpx4 mRNA 3' UTR. The reduction of NSUN2-mediated Gpx4 mRNA m5C methylation abrogates the interaction between SBP2 and the selenocysteine insertion sequence (SECIS) and leads to inhibition of GPX4 protein expression. Lower GPX4 expression promotes hepatocyte Ferroptosis in vivo and in vitro, which is reversed by restoration of NSUN2. These findings shed LIGHT on the mechanism of NSUN2 degradation and also indicate that the STUB1-NSUN2-GPX4 axis plays a regulatory role in hepatocyte Ferroptosis.

Keywords

CP: Molecular biology.

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