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

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Listed:
  • Yongfei Yang

    (Beijing Institute of Technology
    Beijing Institute of Biotechnology)

  • Meiying Luo

    (Beijing Institute of Technology
    Beijing Institute of Biotechnology)

  • 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)

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.

Suggested Citation

  • Yongfei Yang & Meiying Luo & Kexin Zhang & Jun Zhang & Tongtong Gao & Douglas O’ Connell & Fengping Yao & Changwen Mu & Bingyu Cai & Yuxue Shang & Wei Chen, 2020. "Nedd4 ubiquitylates VDAC2/3 to suppress erastin-induced ferroptosis in melanoma," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-14324-x
    DOI: 10.1038/s41467-020-14324-x
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    Cited by:

    1. Juewon Kim & Yunju Jo & Donghyun Cho & Dongryeol Ryu, 2022. "L-threonine promotes healthspan by expediting ferritin-dependent ferroptosis inhibition in C. elegans," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Jun-Yan Li & Yin Zhao & Sha Gong & Miao-Miao Wang & Xu Liu & Qing-Mei He & Ying-Qin Li & Sheng-Yan Huang & Han Qiao & Xi-Rong Tan & Ming-Liang Ye & Xun-Hua Zhu & Shi-Wei He & Qian Li & Ye-Lin Liang & , 2023. "TRIM21 inhibits irradiation-induced mitochondrial DNA release and impairs antitumour immunity in nasopharyngeal carcinoma tumour models," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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