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

IF 7.5 1区生物学 Q1 CELL BIOLOGY Cell reports Pub Date : 2024-10-24 DOI:10.1016/j.celrep.2024.114885

Xiaotian Zhang, Yihua Zhang, Rongrong Li, Yibo Li, Qi Wang, Ying Wang, Xinying Chen, Weihua Wang, Erli Pang, Yanyan Li, Jia Wang, Jinping Zheng, Junjie Zhang

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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.

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STUB1 介导的 NSUN2 泛素化和降解通过减少 Gpx4 mRNA 的 m5C 甲基化促进肝细胞铁变态反应。

铁中毒是一种铁依赖性细胞死亡，是由于细胞膜上的磷脂发生过氧化反应而导致的。本研究发现，NSUN2 的蛋白水平在肝细胞铁变态反应中显著下降。这是由于 STUB1 介导了 NSUN2 在赖氨酸 457 和 654 处的泛素化，促进了 NSUN2 在铁变态反应中的降解。硒蛋白谷胱甘肽过氧化物酶 4（GPX4）是铁突变的一个重要抑制因子。我们发现，下调 NSUN2 会减少 Gpx4 mRNA 3' UTR 的 m5C 甲基化。NSUN2 介导的 Gpx4 mRNA m5C 甲基化的减少会削弱 SBP2 与硒半胱氨酸插入序列（SECIS）之间的相互作用，并导致 GPX4 蛋白表达受到抑制。较低的 GPX4 表达会促进肝细胞体内和体外的铁变态反应，而 NSUN2 的恢复会逆转这种现象。这些发现揭示了NSUN2降解的机制，同时也表明STUB1-NSUN2-GPX4轴在肝细胞铁变态反应中起着调节作用。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.