School of Life Sciences, Sichuan University, Chengdu, 610041, China.
State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China.
Redox Biol. 2024 Jul;73:103182. doi: 10.1016/j.redox.2024.103182. Epub 2024 May 8.
Ferroptosis is an iron-dependent programmed cell death (PCD) enforced by lipid peroxidation accumulation. Transferrin receptor (TFRC), one of the signature proteins of ferroptosis, is abundantly expressed in hepatocellular carcinoma (HCC). However, post-translational modification (PTM) of TFRC and the underlying mechanisms for ferroptosis regulation remain less understood. In this study, we found that TFRC undergoes O-GlcNAcylation, influencing Erastin-induced ferroptosis sensitivity in hepatocytes. Further mechanistic studies found that Erastin can trigger de-O-GlcNAcylation of TFRC at serine 687 (Ser687), which diminishes the binding of ubiquitin E3 ligase membrane-associated RING-CH8 (MARCH8) and decreases polyubiquitination on lysine 665 (Lys665), thereby enhancing TFRC stability that favors labile iron accumulation. Therefore, our findings report O-GlcNAcylation on an important regulatory protein of ferroptosis and reveal an intriguing mechanism by which HCC ferroptosis is controlled by an iron metabolism pathway.
铁死亡是一种由脂质过氧化积累引起的铁依赖性程序性细胞死亡（PCD）。转铁蛋白受体（TFRC）是铁死亡的标志性蛋白之一，在肝细胞癌（HCC）中大量表达。然而，TFRC 的翻译后修饰（PTM）和铁死亡调控的潜在机制仍知之甚少。在这项研究中，我们发现 TFRC 发生 O-GlcNAcylation，影响 Erastin 诱导的肝细胞铁死亡敏感性。进一步的机制研究发现，Erastin 可以触发 TFRC 在丝氨酸 687（Ser687）处去 O-GlcNAcylation，从而减少泛素 E3 连接酶膜相关环指蛋白 8（MARCH8）与赖氨酸 665（Lys665）的结合，减少赖氨酸 665（Lys665）上的多泛素化，从而增强 TFRC 的稳定性，有利于不稳定铁的积累。因此，我们的研究结果报道了铁死亡重要调节蛋白的 O-GlcNAcylation，并揭示了 HCC 铁死亡受铁代谢途径调控的一种有趣机制。
