CRISPR screening identifies PRMT1 as a key pro-ferroptotic gene via a two-layer regulatory mechanism
Xin Zhang,
Yajun Duan,
Su Li,
Zhenyuan Zhang,
Linyuan Peng,
Xiaoyu Ma,
Tianzhi Wang,
Siliang Xiang,
Guo Chen,
Danyang Zhou,
Desheng Lu,
Minxian Qian,
Zhongyuan Wang
Affiliations
Xin Zhang
State Key Laboratory of Natural Medicines, Department of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China; Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Cancer Research Center, Department of Pharmacology, Shenzhen University Medical School, Shenzhen 518055, China
Yajun Duan
State Key Laboratory of Natural Medicines, Department of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China
Su Li
State Key Laboratory of Natural Medicines, Department of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China
Zhenyuan Zhang
State Key Laboratory of Natural Medicines, Department of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China
Linyuan Peng
State Key Laboratory of Natural Medicines, Department of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China
Xiaoyu Ma
State Key Laboratory of Natural Medicines, Department of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China
Tianzhi Wang
State Key Laboratory of Natural Medicines, Department of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China
Siliang Xiang
State Key Laboratory of Natural Medicines, Department of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China
Guo Chen
School of Biopharmacy, China Pharmaceutical University, Nanjing 211198, China
Danyang Zhou
Department of Respiratory, Nanjing First Hospital, China Pharmaceutical University, Nanjing 210012, China
Desheng Lu
Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Cancer Research Center, Department of Pharmacology, Shenzhen University Medical School, Shenzhen 518055, China; Corresponding author
Minxian Qian
State Key Laboratory of Natural Medicines, Department of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China; Corresponding author
Zhongyuan Wang
State Key Laboratory of Natural Medicines, Department of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China; Corresponding author
Summary: Ferroptosis is a form of nonapoptotic cell death characterized by iron-dependent peroxidation of polyunsaturated phospholipids. However, much remains unknown about the regulators of ferroptosis. Here, using CRISPR-Cas9-mediated genetic screening, we identify protein arginine methyltransferase 1 (PRMT1) as a crucial promoter of ferroptosis. We find that PRMT1 decreases the expression of solute carrier family 7 member 11 (SLC7A11) to limit the abundance of intracellular glutathione (GSH). Moreover, we show that PRMT1 interacts with ferroptosis suppressor protein 1 (FSP1), a GSH-independent ferroptosis suppressor, to inhibit the membrane localization and enzymatic activity of FSP1 through arginine dimethylation at R316, thus reducing CoQ10H2 content and inducing ferroptosis sensitivity. Importantly, genetic depletion or pharmacological inhibition of PRMT1 in mice prevents ferroptotic events in the liver and improves the overall survival under concanavalin A (ConA) exposure. Hence, our findings suggest that PRMT1 is a key regulator of ferroptosis and a potential target for antiferroptosis therapeutics.
