USP25 regulates Wnt signaling by controlling the stability of tankyrases.
USP25 regulates Wnt signaling by controlling the stability of tankyrases.
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DOI：
10.1101/gad.300889.117
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发表时间：
2017-05-15
影响因子：
10.5
通讯作者：
Yuan J
中科院分区：
文献类型：
--
作者：
Xu D;Liu J;Fu T;Shan B;Qian L;Pan L;Yuan J
在这里，Xu等人发现USP25，一种泛素特异性蛋白酶，作为Wnt -β-catenin信号传导的正调节因子。他们发现USP25直接与坦克酶相互作用，促进其去泛素化和稳定，USP25缺乏可以促进坦克酶的降解和随后的Axin的稳定，以拮抗Wnt信号。他们的发现为调控坦克酶周转和Wnt -β连环蛋白途径的分子机制提供了新的见解。Wnt信号通路的异常激活在人类癌症的发展中起着重要作用。Wnt信号是由轴蛋白负调控的，轴蛋白是一种支架蛋白，控制着β-连环蛋白破坏的限速步骤，而β-连环蛋白是Wnt通路的中心激活剂。在wnt刺激的细胞中，轴蛋白被tankyase介导的多聚核糖基（ADP-ribosyl）快速修饰，这促进了轴蛋白的蛋白质水解和随后的β-catenin的稳定。因此，调节储罐酶的水平和活性在控制Wnt信号传导方面具有重要的机械意义。在这里，我们发现泛素特异性蛋白酶25 （USP25）是Wnt/β-catenin信号传导的正调节因子。我们发现USP25直接与罐酶相互作用，促进其去泛素化和稳定。我们证明，USP25缺乏可以促进tankrase的降解和随后的轴蛋白的稳定，从而拮抗Wnt信号。我们通过x射线晶体结构测定进一步表征了TNKS1和USP25之间的相互作用。我们的研究结果为tankyrase的分子机制调控提供了重要的新见解，以及通过拮抗tankyrase与USP25的相互作用来调节Wnt/β-catenin通路的可能性。
Here, Xu et al. identified USP25, a ubiquitin-specific protease, as a positive regulator of Wnt–β-catenin signaling. They found that USP25 directly interacted with tankyrases to promote their deubiquitination and stabilization, and USP25 deficiency could promote the degradation of tankyrases and consequent stabilization of Axin to antagonize Wnt signaling. Their findings provide new insights into the molecular mechanism that regulates the turnover of tankyrases and the Wnt–β catenin pathway. Aberrant activation of the Wnt signaling pathway plays an important role in human cancer development. Wnt signaling is negatively regulated by Axin, a scaffolding protein that controls a rate-limiting step in the destruction of β-catenin, the central activator of the Wnt pathway. In Wnt-stimulated cells, Axin is rapidly modified by tankyrase-mediated poly(ADP-ribosyl)ation, which promotes the proteolysis of Axin and consequent stabilization of β-catenin. Thus, regulation of the levels and activity of tankyrases is mechanistically important in controlling Wnt signaling. Here, we identify ubiquitin-specific protease 25 (USP25) as a positive regulator of Wnt/β-catenin signaling. We found that USP25 directly interacted with tankyrases to promote their deubiquitination and stabilization. We demonstrated that USP25 deficiency could promote the degradation of tankyrases and consequent stabilization of Axin to antagonize Wnt signaling. We further characterized the interaction between TNKS1 and USP25 by X-ray crystal structure determination. Our results provide important new insights into the molecular mechanism that regulates the turnover of tankyrases and the possibility of targeting the stability of tankyrases by antagonizing their interaction with USP25 to modulate the Wnt/β-catenin pathway.