Nedd4 ubiquitylates VDAC2/3 to suppress erastin-induced ferroptosis in melanoma

Yongfei Yang (), Meiying Luo, Kexin Zhang, Jun Zhang, Tongtong Gao, Douglas O’ Connell, Fengping Yao, Changwen Mu, Bingyu Cai, Yuxue Shang and Wei Chen ()
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Yongfei Yang: Beijing Institute of Technology
Meiying Luo: Beijing Institute of Technology
Kexin Zhang: Beijing Institute of Technology
Jun Zhang: Beijing Institute of Biotechnology
Tongtong Gao: Beijing Institute of Technology
Douglas O’ Connell: Touro University
Fengping Yao: Beijing Institute of Technology
Changwen Mu: Beijing Institute of Technology
Bingyu Cai: Beijing Institute of Technology
Yuxue Shang: Beijing Institute of Technology
Wei Chen: Beijing Institute of Biotechnology

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract Ferroptosis is a newly defined form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides. Erastin, the ferroptosis activator, binds to voltage-dependent anion channels VDAC2 and VDCA3, but treatment with erastin can result in the degradation of the channels. Here, the authors show that Nedd4 is induced following erastin treatment, which leads to the ubiquitination and subsequent degradation of the channels. Depletion of Nedd4 limits the protein degradation of VDAC2/3, which increases the sensitivity of cancer cells to erastin. By understanding the molecular mechanism of erastin-induced cellular resistance, we can discover how cells adapt to new molecules to maintain homeostasis. Furthermore, erastin-induced resistance mediated by FOXM1-Nedd4-VDAC2/3 negative feedback loop provides an initial framework for creating avenues to overcome the drug resistance of ferroptosis activators.

Date: 2020
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DOI: 10.1038/s41467-020-14324-x

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