Abstract：
Ferroptosis plays important roles both in normal physiology and multiple human diseases. It is well known that selenoprotein named glutathione peroxidase 4 (GPX4) is a crucial regulator for ferroptosis. However, it remains unknown whether other selenoproteins responsible for the regulation of ferroptosis, particularly in gut diseases. In this study, it is observed that Selenoprotein I (Selenoi) prevents ferroptosis by maintaining ether lipids homeostasis. Specific deletion of Selenoi in intestinal epithelial cells induced the occurrence of ferroptosis, leading to impaired intestinal regeneration and compromised colonic tumor growth. Mechanistically, Selenoi deficiency causes a remarkable decrease in ether-linked phosphatidylethanolamine (ePE) and a marked increase in ether-linked phosphatidylcholine (ePC). The imbalance of ePE and ePC results in the upregulation of phospholipase A2, group IIA (Pla2g2a) and group V (Pla2g5), as well as arachidonate-15-lipoxygenase (Alox15), which give rise to excessive lipid peroxidation. Knockdown of PLA2G2A, PLA2G5, or ALOX15 can reverse the ferroptosis phenotypes, suggesting that they are downstream effectors of SELENOI. Strikingly, GPX4 overexpression cannot rescue the ferroptosis phenotypes of SELENOI-knockdown cells, while SELENOI overexpression can partially rescue GPX4-knockdown-induced ferroptosis. It suggests that SELENOI prevents ferroptosis independent of GPX4. Taken together, these findings strongly support the notion that SELENOI functions as a novel suppressor of ferroptosis during colitis and colon tumorigenesis.
摘要：
铁凋亡在正常生理和多种人类疾病中起着重要作用。众所周知，称为谷胱甘肽过氧化物酶4（GPX4）的硒蛋白是铁凋亡的关键调节剂。然而,目前尚不清楚是否有其他硒蛋白负责铁凋亡的调节，特别是在肠道疾病中。在这项研究中,观察到硒蛋白I（Selenoi）通过维持醚脂质稳态来防止铁凋亡。肠上皮细胞中硒的特异性缺失诱导了铁凋亡的发生，导致肠道再生受损和结肠肿瘤生长受损。机械上,硒醇缺乏导致醚连接的磷脂酰乙醇胺（ePE）的显着减少和醚连接的磷脂酰胆碱（ePC）的显着增加。ePE和ePC的不平衡导致磷脂酶A2，IIA组（Pla2g2a）和V组（Pla2g5）的上调，以及花生四烯酸-15-脂氧合酶（Alox15），这会导致过度的脂质过氧化。PLA2G2A的击倒，PLA2G5或ALOX15可以逆转铁凋亡表型，表明它们是SELENOI的下游效应器。引人注目的是，GPX4过表达不能挽救SELENOI敲低细胞的铁凋亡表型，而SELENOI过表达可以部分挽救GPX4敲低诱导的铁细胞凋亡。这表明SELENOI独立于GPX4预防铁死亡。一起来看,这些发现强烈支持了SELENOI在结肠炎和结肠肿瘤发生过程中作为一种新的铁性凋亡抑制因子的观点.
