TY - JOUR
T1 - Deubiquitination of Ci/Gli by Usp7/HAUSP Regulates Hedgehog Signaling
AU - Zhou, Zizhang
AU - Yao, Xia
AU - Li, Shuang
AU - Xiong, Yue
AU - Dong, Xiaohua
AU - Zhao, Yun
AU - Jiang, Jin
AU - Zhang, Qing
N1 - Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/7/6
Y1 - 2015/7/6
N2 - 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.
AB - 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.
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U2 - 10.1016/j.devcel.2015.05.016
DO - 10.1016/j.devcel.2015.05.016
M3 - Article
C2 - 26120032
AN - SCOPUS:84942425852
SN - 1534-5807
VL - 34
SP - 58
EP - 72
JO - Developmental cell
JF - Developmental cell
IS - 1
ER -