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SKP2- and OTUD1-regulated non-proteolytic ubiquitination of YAP promotes YAP nuclear localization and activity

Author

Listed:
  • Fan Yao

    (The University of Texas MD Anderson Cancer Center)

  • Zhicheng Zhou

    (The University of Texas MD Anderson Cancer Center)

  • Jongchan Kim

    (The University of Texas MD Anderson Cancer Center)

  • Qinglei Hang

    (The University of Texas MD Anderson Cancer Center)

  • Zhenna Xiao

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences)

  • Baochau N. Ton

    (The University of Texas MD Anderson Cancer Center)

  • Liang Chang

    (The University of Texas MD Anderson Cancer Center)

  • Na Liu

    (The University of Texas MD Anderson Cancer Center)

  • Liyong Zeng

    (The University of Texas MD Anderson Cancer Center)

  • Wenqi Wang

    (University of California)

  • Yumeng Wang

    (The University of Texas MD Anderson Cancer Center)

  • Peijing Zhang

    (The University of Texas MD Anderson Cancer Center
    Huazhong University of Science and Technology)

  • Xiaoyu Hu

    (The University of Texas MD Anderson Cancer Center)

  • Xiaohua Su

    (The University of Texas MD Anderson Cancer Center)

  • Han Liang

    (The University of Texas MD Anderson Cancer Center)

  • Yutong Sun

    (The University of Texas MD Anderson Cancer Center)

  • Li Ma

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences)

Abstract

Dysregulation of YAP localization and activity is associated with pathological conditions such as cancer. Although activation of the Hippo phosphorylation cascade is known to cause cytoplasmic retention and inactivation of YAP, emerging evidence suggests that YAP can be regulated in a Hippo-independent manner. Here, we report that YAP is subject to non-proteolytic, K63-linked polyubiquitination by the SCFSKP2 E3 ligase complex (SKP2), which is reversed by the deubiquitinase OTUD1. The non-proteolytic ubiquitination of YAP enhances its interaction with its nuclear binding partner TEAD, thereby inducing YAP’s nuclear localization, transcriptional activity, and growth-promoting function. Independently of Hippo signaling, mutation of YAP’s K63-linkage specific ubiquitination sites K321 and K497, depletion of SKP2, or overexpression of OTUD1 retains YAP in the cytoplasm and inhibits its activity. Conversely, overexpression of SKP2 or loss of OTUD1 leads to nuclear localization and activation of YAP. Altogether, our study sheds light on the ubiquitination-mediated, Hippo-independent regulation of YAP.

Suggested Citation

  • Fan Yao & Zhicheng Zhou & Jongchan Kim & Qinglei Hang & Zhenna Xiao & Baochau N. Ton & Liang Chang & Na Liu & Liyong Zeng & Wenqi Wang & Yumeng Wang & Peijing Zhang & Xiaoyu Hu & Xiaohua Su & Han Lian, 2018. "SKP2- and OTUD1-regulated non-proteolytic ubiquitination of YAP promotes YAP nuclear localization and activity," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04620-y
    DOI: 10.1038/s41467-018-04620-y
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    Cited by:

    1. Alexander Vdovin & Tomas Jelinek & David Zihala & Tereza Sevcikova & Michal Durech & Hana Sahinbegovic & Renata Snaurova & Dhwani Radhakrishnan & Marcello Turi & Zuzana Chyra & Tereza Popkova & Ondrej, 2022. "The deubiquitinase OTUD1 regulates immunoglobulin production and proteasome inhibitor sensitivity in multiple myeloma," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Rui Li & Jingchen Shao & Young-June Jin & Haruya Kawase & Yu Ting Ong & Kerstin Troidl & Qi Quan & Lei Wang & Remy Bonnavion & Astrid Wietelmann & Francoise Helmbacher & Michael Potente & Johannes Gra, 2023. "Endothelial FAT1 inhibits angiogenesis by controlling YAP/TAZ protein degradation via E3 ligase MIB2," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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