Deubiquitination of Ci/Gli by Usp7/HAUSP Regulates Hedgehog Signaling

Zizhang Zhou, Xia Yao, Shuang Li, Yue Xiong, Xiaohua Dong, Yun Zhao, Jin Jiang, Qing Zhang

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Hedgehog (Hh) signaling plays essential roles in animal development and tissue homeostasis, and its misregulation causes congenital diseases and cancers. Regulation of the ubiquitin/proteasome-mediated proteolysis of Ci/Gli transcription factors is central to Hh signaling, but whether deubiquitinase is involved in this process remains unknown. Here, we show that Hh stimulates the binding of a ubiquitin-specific protease Usp7 to Ci, which positively regulates Hh signaling activity through inhibiting Ci ubiquitination and degradation mediated by both Slimb-Cul1 and Hib-Cul3 E3 ligases. Furthermore, we find that Usp7 forms a complex with GMP-synthetase (GMPS) to promote Hh pathway activity. Finally, we show that the mammalian counterpart of Usp7, HAUSP, positively regulates Hh signaling by modulating Gli ubiquitination and stability. Our findings reveal a conserved mechanism by which Ci/Gli is stabilized by a deubiquitination enzyme and identify Usp7/HUASP as a critical regulator of Hh signaling and potential therapeutic target for Hh-related cancers.

Original languageEnglish (US)
Pages (from-to)58-72
Number of pages15
JournalDevelopmental Cell
Volume34
Issue number1
DOIs
StatePublished - Jul 6 2015

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Hedgehogs
GMP synthase (glutamine-hydrolyzing)
Tissue homeostasis
Ubiquitin-Specific Proteases
Ubiquitination
Proteolysis
Ubiquitin-Protein Ligases
Proteasome Endopeptidase Complex
Ubiquitin
Animals
Transcription Factors
Haemophilus influenzae type b
Degradation
Enzymes
Neoplasms
Homeostasis

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Zhou, Z., Yao, X., Li, S., Xiong, Y., Dong, X., Zhao, Y., ... Zhang, Q. (2015). Deubiquitination of Ci/Gli by Usp7/HAUSP Regulates Hedgehog Signaling. Developmental Cell, 34(1), 58-72. https://doi.org/10.1016/j.devcel.2015.05.016

Deubiquitination of Ci/Gli by Usp7/HAUSP Regulates Hedgehog Signaling. / Zhou, Zizhang; Yao, Xia; Li, Shuang; Xiong, Yue; Dong, Xiaohua; Zhao, Yun; Jiang, Jin; Zhang, Qing.

In: Developmental Cell, Vol. 34, No. 1, 06.07.2015, p. 58-72.

Research output: Contribution to journalArticle

Zhou, Z, Yao, X, Li, S, Xiong, Y, Dong, X, Zhao, Y, Jiang, J & Zhang, Q 2015, 'Deubiquitination of Ci/Gli by Usp7/HAUSP Regulates Hedgehog Signaling', Developmental Cell, vol. 34, no. 1, pp. 58-72. https://doi.org/10.1016/j.devcel.2015.05.016
Zhou, Zizhang ; Yao, Xia ; Li, Shuang ; Xiong, Yue ; Dong, Xiaohua ; Zhao, Yun ; Jiang, Jin ; Zhang, Qing. / Deubiquitination of Ci/Gli by Usp7/HAUSP Regulates Hedgehog Signaling. In: Developmental Cell. 2015 ; Vol. 34, No. 1. pp. 58-72.
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