Zinc transporter ZIP7 is a novel determinant of ferroptosis
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<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>
Published Version (Please cite this version)10.1038/s41419-021-03482-5
Publication InfoChen, Po-Han; Wu, Jianli; Xu, Yitong; Ding, Chien-Kuang Cornelia; Mestre, Alexander A; Lin, Chao-Chieh; ... Chi, Jen-Tsan (2021). Zinc transporter ZIP7 is a novel determinant of ferroptosis. Cell Death & Disease, 12(2). 10.1038/s41419-021-03482-5. Retrieved from https://hdl.handle.net/10161/22377.
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Jen-Tsan Ashley Chi
Professor in Molecular Genetics and Mirobiology
We are using functional genomic approaches to investigate the nutrient signaling and stress adaptations of cancer cells when exposed to various nutrient deprivations and microenvironmental stress conditions. Recently, we focus on two areas. First, we are elucidating the genetic determinants and disease relevance of ferroptosis, a newly recognized form of cell death. Second, we have identified the mammalian stringent response pathway which is highly similar to bacterial stringent response, but
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