Department of Chemistry, The Scripps Research Institute, San Diego, CA, USA.
ħ Bioconsulting, LLC, Stillwater, MN, USA.
Nat Chem Biol. 2023 Mar;19(3):378-388. doi: 10.1038/s41589-022-01253-7. Epub 2023 Feb 13.
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.
铁死亡是一种依赖铁的细胞死亡形式，由多不饱和脂肪酸（PUFA）磷脂的氧化驱动。大规模的遗传筛选揭示了 PUFA 醚磷脂（ePL）在促进铁死亡方面的特殊作用。然而，人们对参与 PUFA-ePL 生成的酶的了解仍不完整。在这里，我们通过遗传依赖图谱的途径挖掘、AlphaFold 引导的结构预测和靶向脂质组学的组合，表明未被表征的跨膜蛋白 TMEM164（其遗传缺失已被证明可保护细胞免受铁死亡）是一种半胱氨酸活性中心酶，它选择性地将 C20:4 酰基链从磷脂酰胆碱转移到溶酶体 ePL 上，以产生 PUFA ePL。在一组铁死亡敏感的癌细胞系中，TMEM164 的基因缺失导致 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从铁死亡中不同程度的保护，支持 C20:4 ePL 在这种细胞死亡形式中发挥重要但有背景的作用。
