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

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 Liang, Yutong Sun, Li Ma

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article number2269
JournalNature communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

Fingerprint

Ubiquitination
Chemical activation
Phosphorylation
Ubiquitin-Protein Ligases
activation
phosphorylation
cytoplasm
mutations
linkages
deactivation
emerging
cascades
Cytoplasm
depletion
cancer
Mutation
causes
Neoplasms
interactions
growth promoting activity

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

SKP2- and OTUD1-regulated non-proteolytic ubiquitination of YAP promotes YAP nuclear localization and activity. / Yao, Fan; Zhou, Zhicheng; Kim, Jongchan; Hang, Qinglei; Xiao, Zhenna; Ton, Baochau N.; Chang, Liang; Liu, Na; Zeng, Liyong; Wang, Wenqi; Wang, Yumeng; Zhang, Peijing; Hu, Xiaoyu; Su, Xiaohua; Liang, Han; Sun, Yutong; Ma, Li.

In: Nature communications, Vol. 9, No. 1, 2269, 01.12.2018.

Research output: Contribution to journalArticle

Yao, F, Zhou, Z, Kim, J, Hang, Q, Xiao, Z, Ton, BN, Chang, L, Liu, N, Zeng, L, Wang, W, Wang, Y, Zhang, P, Hu, X, Su, X, Liang, H, Sun, Y & Ma, L 2018, 'SKP2- and OTUD1-regulated non-proteolytic ubiquitination of YAP promotes YAP nuclear localization and activity', Nature communications, vol. 9, no. 1, 2269. https://doi.org/10.1038/s41467-018-04620-y
Yao, Fan ; Zhou, Zhicheng ; Kim, Jongchan ; Hang, Qinglei ; Xiao, Zhenna ; Ton, Baochau N. ; Chang, Liang ; Liu, Na ; Zeng, Liyong ; Wang, Wenqi ; Wang, Yumeng ; Zhang, Peijing ; Hu, Xiaoyu ; Su, Xiaohua ; Liang, Han ; Sun, Yutong ; Ma, Li. / SKP2- and OTUD1-regulated non-proteolytic ubiquitination of YAP promotes YAP nuclear localization and activity. In: Nature communications. 2018 ; Vol. 9, No. 1.
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