泛素特异性蛋白酶 4（USP4）是 Wnt 信号通路中的一个新成员。
The ubiquitin specific protease 4 (USP4) is a new player in the Wnt signalling pathway.
机构信息
Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
出版信息
J Cell Mol Med. 2009 Aug;13(8B):1886-95. doi: 10.1111/j.1582-4934.2009.00682.x.
The canonical Wnt signalling pathway is essential for cell fate determination during embryonic development and for the maintenance of adult tissue homeostasis. Deregulation of Wnt signalling leads to developmental defects and is associated with various types of cancer. Here we have used an RNA interference (RNAi) library specifically targeting human deubiquitinating enzymes (DUBs) to screen for new regulators of the canonical Wnt signalling pathway. We found that suppression of the ubiquitin specific protease 4 (USP4) activates beta-catenin dependent transcription. We also show that USP4 is a DUB with dual hydrolysing activity for K(48)- and K(63)-conjugated polyubiquitin chains and interacts with two known Wnt signalling components: the Nemo like kinase (Nlk) and the transcription factor (T-cell factor 4 [TCF4]). Overexpression of a catalytically active Nlk promotes nuclear accumulation of USP4 whereas a subpopulation of TCF4 is a substrate of USP4-dependent deubiquitination. Thus, modulation of USP4 expression may provide a new means to interfere with canonical Wnt signalling in a variety of physiological and pathological conditions.
经典 Wnt 信号通路对于胚胎发育过程中的细胞命运决定以及成人组织稳态的维持至关重要。Wnt 信号通路的失调会导致发育缺陷，并与各种类型的癌症有关。在这里，我们使用了一种专门针对人类去泛素化酶（DUBs）的 RNA 干扰（RNAi）文库，筛选经典 Wnt 信号通路的新调节因子。我们发现，抑制泛素特异性蛋白酶 4（USP4）可激活β-连环蛋白依赖性转录。我们还表明，USP4 是一种具有双重水解活性的 DUB，可水解 K（48）-和 K（63）-连接的多泛素链，并与两个已知的 Wnt 信号成分相互作用：Nemo 样激酶（Nlk）和转录因子（T 细胞因子 4 [TCF4]）。具有催化活性的 Nlk 的过表达促进了 USP4 的核积累，而 TCF4 的亚群是 USP4 依赖性去泛素化的底物。因此，USP4 表达的调节可能为在各种生理和病理条件下干扰经典 Wnt 信号提供一种新方法。
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