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 and Li Ma ()
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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
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
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

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04620-y

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