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bioRxiv · 10.1101/2022.07.06.498872

TMEM164 is an acyltransferase that forms ferroptotic polyunsaturated ether phospholipids

Reed, A.·Ware, T.·Li, H.·Bazan, J. F.·Cravatt, B. F.
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Abstract

Ferroptosis is an iron-dependent form of cell death driven by the oxidation of polyunsaturated (PUFA) phospholipids. Large-scale genetic screens have pointed to 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 furnish PUFA-ePLs. TMEM164-null cells show substantial reductions in PUFA-ePLs, but not PUFA ester phospholipids, supporting that the selective suppression of PUFA-ePLs is sufficient to protect cells from ferroptosis and designating TMEM164 as a key enzyme specifically responsible for regulating this class of lipids.

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Reed, A., Ware, T., Li, H., Bazan, J. F., Cravatt, B. F.. 2022-07-06. TMEM164 is an acyltransferase that forms ferroptotic polyunsaturated ether phospholipids. https://doi.org/10.1101/2022.07.06.498872

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