Zinc transporter ZIP7 is a novel determinant of ferroptosis

• Published in: Cell death & disease Vol. 12; no. 2; p. 198
• Main Authors: Chen, Po-Han, Wu, Jianli, Xu, Yitong, Ding, Chien-Kuang Cornelia, Mestre, Alexander A., Lin, Chao-Chieh, Yang, Wen-Hsuan, Chi, Jen-Tsan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.02.2021; Springer Nature B.V; Nature Publishing Group
• Subjects: 13; 38; 38/89; 38/91; 631/337/2019; 631/80/82/23; 631/80/82/2344; Activating transcription factor 3; Antibodies; Biochemistry; Biomedical and Life Sciences; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - metabolism; Carcinoma, Renal Cell - pathology; Cation Transport Proteins - antagonists & inhibitors; Cation Transport Proteins - genetics; Cation Transport Proteins - metabolism; Cell Biology; Cell Culture; Cell death; Cell Line, Tumor; Chelating Agents - pharmacology; Chelation; Cytosol; Endoplasmic reticulum; Endoplasmic Reticulum - genetics; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum - pathology; Female; Ferroptosis; Ferroptosis - drug effects; Gene Expression Regulation, Neoplastic; Genomes; Heavy metals; Homeostasis; Humans; Immunology; Iron; Kidney cancer; Kidney Neoplasms - genetics; Kidney Neoplasms - metabolism; Kidney Neoplasms - pathology; Life Sciences; Lipid peroxidation; Membrane Proteins - genetics; Membrane Proteins - metabolism; Oxidative stress; Phenotypes; RNA-mediated interference; Supplements; Zinc; Zinc - metabolism; Zinc transporter
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-021-03482-5

Ferroptosis is a newly described form of regulated cell death triggered by oxidative stresses and characterized by extensive lipid peroxidation and membrane damages. The name of ferroptosis indicates that the ferroptotic death process depends on iron, but not other metals, as one of its canonical features. Here, we reported that zinc is also essential for ferroptosis in breast and renal cancer cells. Zinc chelator suppressed ferroptosis, and zinc addition promoted ferroptosis, even during iron chelation. By interrogating zinc-related genes in a genome-wide RNAi screen of ferroptosis, we identified SLC39A7 , encoding ZIP7 that controls zinc transport from endoplasmic reticulum (ER) to cytosol, as a novel genetic determinant of ferroptosis. Genetic and chemical inhibition of the ZIP7 protected cells against ferroptosis, and the ferroptosis protection upon ZIP7 knockdown can be abolished by zinc supplementation. We found that the genetic and chemical inhibition of ZIP7 triggered ER stresses, including the induction of the expression of HERPUD1 and ATF3 . Importantly, the knockdown of HERPUD1 abolished the ferroptosis protection phenotypes of ZIP7 inhibition. Together, we have uncovered an unexpected role of ZIP7 in ferroptosis by maintaining ER homeostasis. These findings may have therapeutic implications for human diseases involving ferroptosis and zinc dysregulations.