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.
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.
Cell Rep. 2024 Nov 26;43(11):114885. doi: 10.1016/j.celrep.2024.114885. Epub 2024 Oct 24.
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 mC methylation of Gpx4 mRNA 3' UTR. The reduction of NSUN2-mediated Gpx4 mRNA mC 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.
铁死亡是一种依赖于铁的细胞死亡，它是由于细胞膜中磷脂的过氧化引起的。在这项研究中，我们发现肝细胞铁死亡时 NSUN2 的蛋白水平显著降低。这归因于 STUB1 介导的 NSUN2 在赖氨酸 457 和 654 处的泛素化，促进铁死亡时 NSUN2 的降解。硒蛋白谷胱甘肽过氧化物酶 4 (GPX4) 是铁死亡的主要抑制因子。我们发现，下调 NSUN2 会减少 Gpx4 mRNA 3'UTR 的 mC 甲基化。减少 NSUN2 介导的 Gpx4 mRNA mC 甲基化会破坏 SBP2 与硒代半胱氨酸插入序列 (SECIS) 的相互作用，从而抑制 GPX4 蛋白的表达。较低的 GPX4 表达促进体内和体外的肝细胞铁死亡，而恢复 NSUN2 则可以逆转这一过程。这些发现揭示了 NSUN2 降解的机制，并表明 STUB1-NSUN2-GPX4 轴在肝细胞铁死亡中起调节作用。
