Zinc transporter ZIP7 is a novel determinant of ferroptosis

Chen, Po-Han

Wu, Jianli

Xu, Yitong

Ding, Chien-Kuang Cornelia

Mestre, Alexander A

Lin, Chao-Chieh

Yang, Wen-Hsuan

Chi, Jen-Tsan

2021-02-21T12:07:23Z

2021-02-21T12:07:23Z

2021-02

2021-02-21T12:07:19Z

<jats:title>Abstract</jats:title><jats:p>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 <jats:italic>SLC39A7</jats:italic>, 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 <jats:italic>HERPUD1</jats:italic> and <jats:italic>ATF3</jats:italic>. Importantly, the knockdown of <jats:italic>HERPUD1</jats:italic> 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.</jats:p>

2041-4889

https://hdl.handle.net/10161/22377

en

Springer Science and Business Media LLC

Cell Death & Disease

10.1038/s41419-021-03482-5

Zinc transporter ZIP7 is a novel determinant of ferroptosis

Journal article

Chi, Jen-Tsan|0000-0003-3433-903X

2

School of Medicine

Duke Cancer Institute

Molecular Genetics and Microbiology

Pharmacology & Cancer Biology

Radiation Oncology

Medicine, Rheumatology and Immunology

Duke

Institutes and Centers

Basic Science Departments

Clinical Science Departments

Medicine

Published

12