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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.  Dev. Cell 34(1): 58--72.
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Research paper

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.

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Obtained with permission from Cell Press.
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PMC4627479 (PMC) (EuropePMC)
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    Publication Type
    Dev. Cell
    Developmental Cell
    Publication Year
    1534-5807 1878-1551
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