O-GlcNAcylation regulates the stability of transferrin receptor (TFRC) to control the ferroptosis in hepatocellular carcinoma cells,Redox Biology

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O-GlcNAcylation regulates the stability of transferrin receptor (TFRC) to control the ferroptosis in hepatocellular carcinoma cells
Redox Biology ( IF 10.7 ) Pub Date : 2024-05-08 , DOI: 10.1016/j.redox.2024.103182
Xunyu Zhou ₁ , Yida Wang ₁ , Xiaoyu Li ₂ , Jing Zhou ₃ , Wanyi Yang ₁ , Xin Wang ₁ , Sitong Jiao ₁ , Weibo Zuo ₁ , Ziming You ₁ , Wantao Ying ₂ , Chuanfang Wu ₁ , Jinku Bao ₁

Affiliation

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.

中文翻译：

O-GlcNAc糖基化调节转铁蛋白受体（TFRC）的稳定性以控制肝癌细胞的铁死亡

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) 和铁死亡调节的潜在机制仍知之甚少。在这项研究中，我们发现 TFRC 发生 O-GlcNAc 酰化，影响肝细胞中 Erastin 诱导的铁死亡敏感性。进一步的机制研究发现，Erastin 可以触发 TFRC 在丝氨酸 687 (Ser687) 处的去-O-GlcNAcylation，从而减少泛素 E3 连接酶膜相关的 RING-CH8 (MARCH8) 的结合，并减少赖氨酸 665 (Lys665) 上的多泛素化，从而增强 TFRC 稳定性，有利于不稳定铁的积累。因此，我们的研究结果报告了铁死亡的重要调节蛋白上的O-GlcNAc糖基化，并揭示了铁代谢途径控制HCC铁死亡的有趣机制。

更新日期：2024-05-08

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