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

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-independ...

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Vydané v:	Nature communications Ročník 9; číslo 1; s. 2269 - 16
Hlavní autori:	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
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	London Nature Publishing Group UK 11.06.2018 Nature Publishing Group Nature Portfolio
Predmet:	38/109 42/89 631/45/612/1254 631/80/2023/2022 631/80/458/582 64/60 82/29 82/83 96/95 Activation Active Transport, Cell Nucleus Adaptor Proteins, Signal Transducing - chemistry Adaptor Proteins, Signal Transducing - genetics Adaptor Proteins, Signal Transducing - metabolism Amino Acid Substitution Animals Binding Sites - genetics Cancer Cell Line Cell Nucleus - metabolism Cytoplasm Deactivation DNA-Binding Proteins - metabolism Female Gene Knockout Techniques HEK293 Cells Humanities and Social Sciences Humans Inactivation Localization Mice multidisciplinary Mutagenesis, Site-Directed Nuclear Proteins - metabolism Phosphoproteins - chemistry Phosphoproteins - genetics Phosphoproteins - metabolism Phosphorylation Protein-Serine-Threonine Kinases - metabolism Proteolysis S-Phase Kinase-Associated Proteins - metabolism Science Science (multidisciplinary) Skp2 protein Transcription Transcription Factors - metabolism Ubiquitin-protein ligase Ubiquitin-Specific Proteases - metabolism Ubiquitination Yes-associated protein
ISSN:	2041-1723, 2041-1723
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Shrnutí:	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 SCF SKP2 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. Regulation of Yes-associated protein (YAP) through the Hippo pathway is well established, but its Hippo-independent regulation remains to be elucidated. Here, the authors show that non-proteolytic ubiquitination presents another means of YAP regulation, promoting its nuclear localization and activity.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-018-04620-y