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

• Published in: Nature communications Vol. 11; no. 1; pp. 433 - 14
• Main Authors: Yang, Yongfei, Luo, Meiying, Zhang, Kexin, Zhang, Jun, Gao, Tongtong, Connell, Douglas O’, Yao, Fengping, Mu, Changwen, Cai, Bingyu, Shang, Yuxue, Chen, Wei
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.01.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/31; 13/51; 13/89; 14; 14/63; 38; 38/77; 38/88; 631/67/1813/1634; 631/80/458/582; 631/80/82; 64/60; Animals; Anion channels; Antineoplastic Agents - pharmacology; Apoptosis; Biodegradation; Cancer therapies; Cell death; Cell Line, Tumor; Degradation; Depletion; Drug resistance; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - physiology; Feedback loops; Female; Ferroptosis; Ferroptosis - drug effects; Ferroptosis - physiology; Forkhead Box Protein M1 - metabolism; Homeostasis; Humanities and Social Sciences; Humans; Ion channels; Iron; Kinases; Lipid peroxidation; Lipids; Melanoma; Melanoma - drug therapy; Melanoma - metabolism; Melanoma - pathology; Mice, Nude; Mitochondrial Membrane Transport Proteins - genetics; Mitochondrial Membrane Transport Proteins - metabolism; multidisciplinary; Mutation; Nedd4 Ubiquitin Protein Ligases - genetics; Nedd4 Ubiquitin Protein Ligases - metabolism; Negative feedback; Piperazines - pharmacology; Proteins; Science; Science (multidisciplinary); Skin cancer; Ubiquitination; Ubiquitination - drug effects; Voltage; 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
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-14324-x

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. Erastin, the ferroptosis activator, binds to voltage gated ion channels CDAC2 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.