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

Fan Yao1, Zhicheng Zhou1, Jongchan Kim1

  • 1Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.

Nature Communications
|June 13, 2018
PubMed

Insights

YAP protein

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Dysregulated YAP localization and activity are linked to cancer.
  • The Hippo pathway controls YAP, but independent regulation exists.

Purpose of the Study:

  • To investigate the role of ubiquitination in YAP regulation independent of the Hippo pathway.
  • To identify the specific E3 ligase and deubiquitinase involved in YAP ubiquitination.

Main Methods:

  • Investigated YAP ubiquitination using SCFSKP2 E3 ligase and OTUD1 deubiquitinase.
  • Utilized site-directed mutagenesis to alter YAP ubiquitination sites (K321, K497).
  • Assessed YAP localization, TEAD interaction, and transcriptional activity through genetic manipulation and biochemical assays.

Main Results:

  • YAP undergoes K63-linked polyubiquitination by SCFSKP2, promoting nuclear localization and activity.
  • OTUD1 reverses this ubiquitination, inhibiting YAP.
  • Mutating YAP's ubiquitination sites or altering SKP2/OTUD1 levels impacts YAP's cytoplasmic retention and activity, independent of Hippo signaling.

Conclusions:

  • Ubiquitination, mediated by SCFSKP2 and OTUD1, represents a novel Hippo-independent mechanism for YAP regulation.
  • Targeting this ubiquitination pathway could offer new therapeutic strategies for YAP-driven pathologies like cancer.

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