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 journalArticlepeer-review

45 Scopus citations

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. Regulation of ubiquitin/proteasome-mediated proteolysis of Ci/Gli transcription factors is central to Hedgehog (Hh) signaling. Zhou et al. implicate the Drosophila deubiquitinase Usp7/HUASP in positive Hh signaling regulation via inhibition of Ci degradation by Slimb-Cul1 and Hib-Cul3 E3 ligases. Usp7/HUASP function is evolutionarily conserved, suggesting it could be a therapeutic target.

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

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Deubiquitination of Ci/Gli by Usp7/HAUSP Regulates Hedgehog Signaling'. Together they form a unique fingerprint.

Cite this