TMEM164是一种酰基转移酶，形成了铁死亡相关的C20:4醚型磷脂。
TMEM164 is an acyltransferase that forms ferroptotic C20:4 ether phospholipids.
发表日期：2023 Mar
作者：
Alex Reed, Timothy Ware, Haoxin Li, J Fernando Bazan, Benjamin F Cravatt
来源：
Nature Chemical Biology
摘要：
Ferroptosis是一种依赖于铁的细胞死亡形式，由多不饱和脂肪酸（PUFA）磷脂氧化驱动。大规模基因筛选揭示了PUFA醚磷脂（ePLs）在促进ferroptosis中的专门作用。然而，对参与PUFA-ePL生产的酶的理解仍然不完整。在这里，我们使用遗传依赖地图路径挖掘、AlphaFold导向的结构预测和有针对性的脂质组学的组合，展示了尚未表征的跨膜蛋白TMEM164-已经显示其基因消融保护细胞免受ferroptosis-是一种半胱氨酸活性中心酶，可选择性地将C20:4酰基链从磷脂酰胆碱转移到裂解ePLs以产生PUFA ePLs。在一组ferroptosis敏感的癌细胞系中去除TMEM164基因导致C20:4 ePL选择性降低，对C20:4二酰基PL的影响最小，这种脂质谱产生了一系列不同程度的ferroptosis保护作用，支持C20:4 ePLs在这种细胞死亡形式中的重要但具有情境化的作用。©2023年作者独家授权给Springer Nature America， Inc。
Ferroptosis is an iron-dependent form of cell death driven by oxidation of polyunsaturated fatty acid (PUFA) phospholipids. Large-scale genetic screens have uncovered a specialized role for PUFA ether phospholipids (ePLs) in promoting ferroptosis. 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-the 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.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.