Regulation of FSP1 myristoylation by NADPH: A novel mechanism for ferroptosis inhibition
Na Liu,
Wei-Long Wu,
Xiao-Rui Wan,
Jing Wang,
Jia-Ni Huang,
Yi-Yue Jiang,
Yi-Chao Sheng,
Jun-Chao Wu,
Zhong-Qin Liang,
Zheng-Hong Qin,
Yan Wang
Affiliations
Na Liu
Department of Pharmacology College of Pharmaceutical Sciences, Suzhou Key Laboratory of Aging and Nervous Diseases, and Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou, Jiangsu, China
Wei-Long Wu
Department of Pharmacology College of Pharmaceutical Sciences, Suzhou Key Laboratory of Aging and Nervous Diseases, and Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou, Jiangsu, China
Xiao-Rui Wan
Department of Pharmacology College of Pharmaceutical Sciences, Suzhou Key Laboratory of Aging and Nervous Diseases, and Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou, Jiangsu, China
Jing Wang
Department of Pharmacology College of Pharmaceutical Sciences, Suzhou Key Laboratory of Aging and Nervous Diseases, and Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou, Jiangsu, China
Jia-Ni Huang
Department of Pharmacology College of Pharmaceutical Sciences, Suzhou Key Laboratory of Aging and Nervous Diseases, and Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou, Jiangsu, China
Yi-Yue Jiang
Department of Pharmacology College of Pharmaceutical Sciences, Suzhou Key Laboratory of Aging and Nervous Diseases, and Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou, Jiangsu, China
Yi-Chao Sheng
Department of Pharmacology College of Pharmaceutical Sciences, Suzhou Key Laboratory of Aging and Nervous Diseases, and Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou, Jiangsu, China
Jun-Chao Wu
Department of Pharmacology College of Pharmaceutical Sciences, Suzhou Key Laboratory of Aging and Nervous Diseases, and Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou, Jiangsu, China
Zhong-Qin Liang
Department of Pharmacology College of Pharmaceutical Sciences, Suzhou Key Laboratory of Aging and Nervous Diseases, and Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou, Jiangsu, China
Zheng-Hong Qin
Department of Pharmacology College of Pharmaceutical Sciences, Suzhou Key Laboratory of Aging and Nervous Diseases, and Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou, Jiangsu, China
Yan Wang
Corresponding author. Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.; Department of Pharmacology College of Pharmaceutical Sciences, Suzhou Key Laboratory of Aging and Nervous Diseases, and Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou, Jiangsu, China
Excitotoxicity is a prevalent pathological event in neurodegenerative diseases. The involvement of ferroptosis in the pathogenesis of excitotoxicity remains elusive. Transcriptome analysis has revealed that cytoplasmic reduced nicotinamide adenine dinucleotide phosphate (NADPH) levels are associated with susceptibility to ferroptosis-inducing compounds. Here we show that exogenous NADPH, besides being reductant, interacts with N-myristoyltransferase 2 (NMT2) and upregulates the N-myristoylated ferroptosis suppressor protein 1 (FSP1). NADPH increases membrane-localized FSP1 and strengthens resistance to ferroptosis. Arg-291 of NMT2 is critical for the NADPH-NMT2-FSP1 axis-mediated suppression of ferroptosis. This study suggests that NMT2 plays a pivotal role by bridging NADPH levels and neuronal susceptibility to ferroptosis. We propose a mechanism by which the NADPH regulates N-myristoylation, which has important implications for ferroptosis and disease treatment.
