Deubiquitination of Ci/Gli by Usp7/HAUSP Regulates Hedgehog Signaling.
Deubiquitination of Ci/Gli by Usp7/HAUSP Regulates Hedgehog Signaling.
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Usp7/HAUSP 对 Ci/Gli 的去泛素化调节 Hedgehog 信号传导。
DOI：
10.1016/j.devcel.2015.05.016
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发表时间：
2015-07
影响因子：
11.8
通讯作者：
Zhang, Qing
中科院分区：
文献类型：
--
作者：
Dong, Xiaohua;Zhao, Yun;Jiang, Jin;Zhang, Qing
HH信号在动物发育和组织动态平衡中起着至关重要的作用，它的错误调控会导致先天性疾病和癌症。调节泛素/蛋白酶体介导的Ci/Gli转录因子的蛋白分解是HH信号转导的核心，但脱泛素酶是否参与这一过程尚不清楚。在这里，我们证明了HH刺激泛素特异性蛋白酶USP7与Ci的结合，这通过抑制SLimd-Cul1和Hib-CUL3E3连接酶介导的Ci泛素化和降解来积极调节HH信号活性。此外，我们还发现USP7与GMP合成酶(GMPS)形成一个复合体来促进HH途径的活性。最后，我们证明了哺乳动物中USP7的对应物Hausp通过调节Gli泛素化和稳定性来积极调节HH信号。我们的发现揭示了Ci/Gli被去泛素化酶稳定的保守机制，并确认USP7/HUASP是HH信号的关键调节因子和HH相关癌症的潜在治疗靶点。
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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影响因子：
11.8
作者：
Qing Zhang;Lei Zhang;B. Wang;Chan-Yen Ou;C. Chien;Jin Jiang
通讯作者：
Qing Zhang;Lei Zhang;B. Wang;Chan-Yen Ou;C. Chien;Jin Jiang
影响因子：
8.8
作者：
Niewiadomski P;Kong JH;Ahrends R;Ma Y;Humke EW;Khan S;Teruel MN;Novitch BG;Rohatgi R
通讯作者：
Rohatgi R
影响因子：
64.8
作者：
Ohlmeyer, JT;Kalderon, D
通讯作者：
Kalderon, D
影响因子：
11.8
作者：
Zhao Zhang;Xiangdong Lv;Wen-chi Yin;Xiaoyun Zhang;Jing Feng;Wenqing Wu;C. Hui;Lei Zhang;
通讯作者：
Zhao Zhang;Xiangdong Lv;Wen-chi Yin;Xiaoyun Zhang;Jing Feng;Wenqing Wu;C. Hui;Lei Zhang;
影响因子：
9.8
作者：
Li S;Chen Y;Shi Q;Yue T;Wang B;Jiang J
通讯作者：
Jiang J