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The covalent modifier Nedd8 is critical for the activation of Smurf1 ubiquitin ligase in tumorigenesis

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  • Ping Xie

    (State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine
    Institute of Cancer Stem Cell, Dalian Medical University)

  • Minghua Zhang

    (State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine)

  • Shan He

    (State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine)

  • Kefeng Lu

    (State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine)

  • Yuhan Chen

    (State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine)

  • Guichun Xing

    (State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine)

  • Yiming Lu

    (State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine)

  • Ping Liu

    (Center of Pharmacy, Chinese PLA General Hospital)

  • Yang Li

    (Beijing Institute of Radiation Medicine)

  • Shaoxia Wang

    (Beijing Institute of Radiation Medicine)

  • Nan Chai

    (School of Life Sciences, Tsinghua University)

  • Jiawei Wu

    (School of Life Sciences, Tsinghua University)

  • Haiteng Deng

    (School of Life Sciences, Tsinghua University)

  • Hong-Rui Wang

    (School of Life Sciences, Xiamen University)

  • Yu Cao

    (State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine)

  • Fei Zhao

    (State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine)

  • Yu Cui

    (State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine)

  • Jian Wang

    (State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine)

  • Fuchu He

    (State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine)

  • Lingqiang Zhang

    (State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine
    Institute of Cancer Stem Cell, Dalian Medical University)

Abstract

Neddylation, the covalent attachment of ubiquitin-like protein Nedd8, of the Cullin-RING E3 ligase family regulates their ubiquitylation activity. However, regulation of HECT ligases by neddylation has not been reported to date. Here we show that the C2-WW-HECT ligase Smurf1 is activated by neddylation. Smurf1 physically interacts with Nedd8 and Ubc12, forms a Nedd8-thioester intermediate, and then catalyses its own neddylation on multiple lysine residues. Intriguingly, this autoneddylation needs an active site at C426 in the HECT N-lobe. Neddylation of Smurf1 potently enhances ubiquitin E2 recruitment and augments the ubiquitin ligase activity of Smurf1. The regulatory role of neddylation is conserved in human Smurf1 and yeast Rsp5. Furthermore, in human colorectal cancers, the elevated expression of Smurf1, Nedd8, NAE1 and Ubc12 correlates with cancer progression and poor prognosis. These findings provide evidence that neddylation is important in HECT ubiquitin ligase activation and shed new light on the tumour-promoting role of Smurf1.

Suggested Citation

  • Ping Xie & Minghua Zhang & Shan He & Kefeng Lu & Yuhan Chen & Guichun Xing & Yiming Lu & Ping Liu & Yang Li & Shaoxia Wang & Nan Chai & Jiawei Wu & Haiteng Deng & Hong-Rui Wang & Yu Cao & Fei Zhao & Y, 2014. "The covalent modifier Nedd8 is critical for the activation of Smurf1 ubiquitin ligase in tumorigenesis," Nature Communications, Nature, vol. 5(1), pages 1-16, September.
  • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4733
    DOI: 10.1038/ncomms4733
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    Cited by:

    1. Yizhang Tang & Xujiang Yu & Liangrui He & Meng Tang & Wenji Yue & Ruitong Chen & Jie Zhao & Qi Pan & Wanwan Li, 2025. "A high-valence bismuth(V) nanoplatform triggers cancer cell death and anti-tumor immune responses with exogenous excitation-free endogenous H2O2- and O2-independent ROS generation," Nature Communications, Nature, vol. 16(1), pages 1-19, December.

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