Department of Oncology, National Engineering Research Center for Nanomedicine, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.
Translational Medicine Center, Shanghai General Hospital, Shanghai JiaoTong University School of Medicine , Shanghai, China.
J Cell Biol. 2023 Nov 6;222(11). doi: 10.1083/jcb.202212072. Epub 2023 Oct 13.
The dependency of cancer cells on iron increases their susceptibility to ferroptosis, thus providing new opportunities for patients with treatment-resistant tumors. However, we show that lipid peroxidation, a hallmark of ferroptosis, was found in various areas of patient samples, indicating the potential resistance of ferroptosis. Using whole deubiquitinases (DUBs) sgRNA screening, we found that loss of ZRANB1 confers cancer cell resistance to ferroptosis. Intriguingly, functional studies revealed that ZRANB1 ubiquitinates and represses SLC7A11 expression as an E3 ubiquitin ligase and that ZRANB1 inhibits glutathione (GSH) synthesis through SLC7A11 degradation, leading to elevated lipid peroxidation and ferroptosis. Deletion of the region (residues 463-584) abolishes the E3 activity of ZRANB1. Moreover, we show that ZRANB1 has lower expression in tumors, which is positively correlated with lipid peroxidation. Collectively, our results demonstrate the role of ZRANB1 in ferroptosis resistance and unveil mechanisms involving modulation of E3 ligase activity through an unconventional catalytic domain.
癌细胞对铁的依赖增加了它们对铁死亡的敏感性，从而为治疗抵抗性肿瘤患者提供了新的机会。然而，我们发现铁死亡的一个标志——脂质过氧化，存在于患者样本的各个区域，这表明铁死亡可能存在抵抗性。通过全泛素酶（DUBs）sgRNA 筛选，我们发现 ZRANB1 的缺失赋予了癌细胞对铁死亡的抗性。有趣的是，功能研究表明，ZRANB1 作为一种 E3 泛素连接酶，泛素化并抑制 SLC7A11 的表达，并且 ZRANB1 通过 SLC7A11 的降解抑制谷胱甘肽（GSH）的合成，导致脂质过氧化和铁死亡的增加。删除该区域（残基 463-584）会使 ZRANB1 的 E3 活性丧失。此外，我们发现 ZRANB1 在肿瘤中的表达较低，这与脂质过氧化呈正相关。总之，我们的研究结果表明了 ZRANB1 在铁死亡抵抗中的作用，并揭示了通过非传统催化结构域调节 E3 连接酶活性的机制。
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