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

Nat Commun. 2020 Jan 23;11(1):433. doi: 10.1038/s41467-020-14324-x.

Yongfei Yang ^# ¹ ², Meiying Luo ^# ³ ⁴, Kexin Zhang ^# ³, Jun Zhang ⁴, Tongtong Gao ³, Douglas O' Connell ⁵, Fengping Yao ³, Changwen Mu ³, Bingyu Cai ³, Yuxue Shang ³, Wei Chen ⁶

Affiliations

1 Key Laboratory of Molecular Medicine and Biotherapy, School of Life Science, Beijing Institute of Technology, Beijing, 100081, China. [email protected].
2 Beijing Institute of Biotechnology, Beijing, 100071, China. [email protected].
3 Key Laboratory of Molecular Medicine and Biotherapy, School of Life Science, Beijing Institute of Technology, Beijing, 100081, China.
4 Beijing Institute of Biotechnology, Beijing, 100071, China.
5 College of Osteopathic Medicine, Touro University, Vallejo, CA, 94592, USA.
6 Beijing Institute of Biotechnology, Beijing, 100071, China. [email protected].
# Contributed equally.

PMID: 31974380 DOI: 10.1038/s41467-020-14324-x

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.

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