TMEM164 is an acyltransferase that forms ferroptotic C20:4 ether phospholipids.
TMEM164 is an acyltransferase that forms ferroptotic C20:4 ether phospholipids.
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DOI：
10.1038/s41589-022-01253-7
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发表时间：
2023-03
影响因子：
14.8
通讯作者：
Cravatt, Benjamin F.
中科院分区：
文献类型：
--
作者：
Reed, Alex;Ware, Timothy;Li, Haoxin;Bazan, J. Fernando;Cravatt, Benjamin F.
铁蛋白沉积症是一种由多不饱和（PUFA）磷脂氧化驱动的铁依赖性细胞死亡形式。大规模的遗传筛选已经揭示了PUFA醚磷脂（ePLs）在促进铁凋亡中的特殊作用。然而，我们对PUFA ePL生产中涉及的酶的理解仍然不完整。在这里，我们使用遗传依赖性图谱的途径挖掘，AlphaFold指导的结构预测和靶向脂质组学的组合显示，未表征的跨膜蛋白TMEM 164-其遗传消融已被证明可以保护细胞免受铁凋亡-是一种半胱氨酸活性中心酶，选择性地将C20：4酰基链从磷脂酰胆碱转移到溶血ePL以产生PUFA-ePL。在一组铁凋亡敏感性癌细胞系中TMEM 164的遗传缺失导致C20：4-ePL的选择性减少，对C20：4-二酰基PL的影响最小，并且这种脂质谱产生了对铁凋亡的可变范围的保护，支持C20：4-ePL在这种形式的细胞死亡中的重要但背景化的作用。
Ferroptosis is an iron-dependent form of cell death driven by oxidation of polyunsaturated (PUFA) phospholipids. Large-scale genetic screens have uncovered a specialized role for PUFA ether phospholipids (ePLs) in promoting ferroptosis. Our understanding of the enzymes involved in PUFA ePL production, however, remains incomplete. Here we show using a combination of pathway mining of genetic dependency maps, AlphaFold-guided structure predictions, and targeted lipidomics that the uncharacterized transmembrane protein TMEM164 – genetic ablation of which has been shown to protect cells from ferroptosis – is a cysteine active-center enzyme that selectively transfers C20:4 acyl chains from phosphatidylcholine to lyso-ePLs to produce PUFA-ePLs. Genetic deletion of TMEM164 across a set of ferroptosis-sensitive cancer cell lines caused selective reductions in C20:4-ePLs with minimal effects on C20:4-diacyl PLs, and this lipid profile produced a variable range of protection from ferroptosis, supportive of an important, but contextualized role for C20:4-ePLs in this form of cell death.
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影响因子：
14.8
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6.5
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影响因子：
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