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; Wei Chen

doi:10.1038/s41467-020-14324-x

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.

Authors

Yongfei Yang^#^{1

2}, Meiying Luo^#^{3

4}, Kexin Zhang^#³, Jun Zhang⁴, Tongtong Gao³, Douglas O' Connell⁵, Fengping Yao³, Changwen Mu³, Bingyu Cai³, Yuxue Shang³, Wei Chen⁶

Affiliations

¹ Key Laboratory of Molecular Medicine and Biotherapy, School of Life Science, Beijing Institute of Technology, Beijing, 100081, China. yangyf@bit.edu.cn.
² Beijing Institute of Biotechnology, Beijing, 100071, China. yangyf@bit.edu.cn.
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. cw0226@foxmail.com.

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Drug Resistance, Neoplasm / drug effects
Drug Resistance, Neoplasm / physiology
Female
Ferroptosis / drug effects
Ferroptosis / physiology
Forkhead Box Protein M1 / metabolism
Humans
Melanoma / drug therapy*
Melanoma / metabolism
Melanoma / pathology
Mice, Nude
Mitochondrial Membrane Transport Proteins / genetics
Mitochondrial Membrane Transport Proteins / metabolism*
Nedd4 Ubiquitin Protein Ligases / genetics
Nedd4 Ubiquitin Protein Ligases / metabolism*
Piperazines / pharmacology*
Ubiquitination / drug effects
Voltage-Dependent Anion Channel 2 / genetics
Voltage-Dependent Anion Channel 2 / metabolism*
Voltage-Dependent Anion Channels / genetics
Voltage-Dependent Anion Channels / metabolism*
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
FOXM1 protein, human
Forkhead Box Protein M1
Mitochondrial Membrane Transport Proteins
Piperazines
VDAC2 protein, human
VDAC3 protein, human
Voltage-Dependent Anion Channel 2
Voltage-Dependent Anion Channels
erastin
Nedd4 Ubiquitin Protein Ligases
Nedd4 protein, human