Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 201210 Shanghai, China.
University of Chinese Academy of Sciences, 100049 Beijing, China.
Proc Natl Acad Sci U S A. 2022 Nov;119(44):e2214227119. doi: 10.1073/pnas.2214227119. Epub 2022 Oct 24.
LUBAC-mediated linear ubiquitination plays a pivotal role in regulation of cell death and inflammatory pathways. Genetic deficiency in LUBAC components leads to severe immune dysfunction or embryonic lethality. LUBAC has been extensively studied for its role in mediating TNF signaling. However, knockout is not able to fully rescue the embryonic lethality of LUBAC deficiency, suggesting that LUBAC may modify additional key cellular substrates in promoting cell survival. GPx4 is an important selenoprotein involved in regulating cellular redox homeostasis in defense against lipid peroxidation-mediated cell death known as ferroptosis. Here we demonstrate that LUBAC deficiency sensitizes to ferroptosis by promoting GPx4 degradation and downstream lipid peroxidation. LUBAC binds and stabilizes GPx4 by modulating its linear ubiquitination both in normal condition and under oxidative stress. Our findings identify GPx4 as a key substrate of LUBAC and a previously unrecognized role of LUBAC-mediated linear ubiquitination in regulating cellular redox status and cell death.
LUBAC 介导的线性泛素化在调节细胞死亡和炎症途径中起着关键作用。LUBAC 成分的遗传缺陷导致严重的免疫功能障碍或胚胎致死。LUBAC 已被广泛研究其在介导 TNF 信号转导中的作用。然而，LUBAC 的缺失并不能完全挽救 LUBAC 缺陷的胚胎致死性，这表明 LUBAC 可能在促进细胞存活方面修饰其他关键细胞底物。GPx4 是一种重要的硒蛋白，参与调节细胞氧化还原稳态，以抵御脂质过氧化介导的细胞死亡，称为铁死亡。在这里，我们证明 LUBAC 缺陷通过促进 GPx4 降解和下游脂质过氧化作用而使细胞对铁死亡敏感。LUBAC 通过调节其在正常条件和氧化应激下的线性泛素化来结合和稳定 GPx4。我们的研究结果将 GPx4 确定为 LUBAC 的关键底物，以及 LUBAC 介导的线性泛素化在调节细胞氧化还原状态和细胞死亡方面的一个先前未被认识的作用。
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