The COP9 Signalosome Mediates β-Catenin Degradation by Deneddylation and Blocks Adenomatous Polyposis coli Destruction via USP15
The COP9 Signalosome Mediates β-Catenin Degradation by Deneddylation and Blocks Adenomatous Polyposis coli Destruction via USP15
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DOI：
10.1016/j.jmb.2009.06.066
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发表时间：
2009-08-28
影响因子：
5.6
通讯作者：
Dubiel, Wolfgang
中科院分区：
文献类型：
--
作者：
Huang, Xiaohua;Langelotz, Corinna;Dubiel, Wolfgang
Wnt/β-连环蛋白信号通路在正常细胞增殖、发育和血管生成中具有重要作用。许多恶性转化，包括散发性结直肠肿瘤，是由肿瘤抑制蛋白腺瘤性结肠息肉病（APC）或β-连环蛋白癌基因突变引起的Wnt途径的组成性激活引起的，最终导致泛素（Ub）蛋白酶体系统（UPS）对β-连环蛋白的降解减少。CON信号体（CSN）通过控制cullin-RING Ub连接酶（CRL）来调节UPS。我们在这里表明，CSN和β-连环蛋白破坏复合物合作，针对β-连环蛋白降解的UPS。与泛素化β-连环蛋白的CRL一起，它们形成负责β-连环蛋白降解的超复合物。Wnt 3A、糖原合成酶激酶3 β抑制剂或CSN介导的去脱氧化突变诱导超复合物的分解和β-连环蛋白的积累。同样，HeLa细胞中CSN的下调导致β-连环蛋白的降解延迟。此外，我们发现CSN的敲除导致APC的加速蛋白水解，APC是β-连环蛋白破坏复合物的重要组分，其被UPS降解为β-连环蛋白。我们在这里表明，APC是稳定的Ub特异性蛋白酶15（USP 15）与CSN。这通过针对USP 15的siRNA寡核苷酸的过表达或通过USP 15突变体的过表达来证明，所述突变体不能降解聚Ub链。因此，CSN控制Wnt/β-连环蛋白信号传导，通过去涡化辅助β-连环蛋白降解超复合物的组装，同时通过CSN相关的USP 15稳定APC。CSN调节β-连环蛋白和APC之间的平衡。这种平衡的紊乱可以通过驱动细胞转化、肿瘤血管生成和转移而导致癌症。提供了一个模型，提出了CSN介导的去eddylation在β-连环蛋白降解超复合物形成中的作用，并通过CSN相关的USP 15保护复合物结合的A-PC。(C)2009爱思唯尔有限公司保留所有权利。
The Wnt/beta-catenin signalling pathway has important roles in normal cellular proliferation, development and angiogenesis. Many malignant transformations, including sporadic colorectal tumours, are caused by constitutive activation of the Wnt route due to mutations in the tumour suppressor protein adenomatous polyposis coli (APC) or the beta-catenin oncogene, ultimately resulting in reduced beta-catenin degradation by the ubiquitin (Ub) proteasome system (UPS). The CON signalosome (CSN) regulates the UPS by controlling cullin-RING Ub ligases (CRLs). We show here that the CSN and the beta-catenin destruction complex cooperate in targeting beta-catenin for degradation by the UPS. Together with the CRL that ubiquitinates beta-catenin, they form a supercomplex responsible for beta-catenin degradation. Wnt3A, glycogen synthase kinase 3 beta inhibitors or mutation of CSN-mediated deneddylation induce the disassembly of the supercomplex and the accumulation of beta-catenin. Likewise, downregulation of the CSN in HeLa cells leads to retarded degradation of beta-catenin. Additionally, we found that the knockdown of the CSN causes accelerated proteolysis of APC, an essential component of the beta-catenin destruction complex, which is degraded by the UPS as beta-catenin. We show here that APC is stabilised by the Ub-specific protease 15 (USP15) associated with the CSN. This is demonstrated by over-expression of siRNA oligonucleotides against USP15 or by over-expression of an USP15 mutant, which is unable to degrade poly-Ub chains. Thus, the CSN controls the Wnt/beta-catenin signalling by assisting the assembly of beta-catenin-degrading supercomplexes by deneddylation and, simultaneously, by stabilising APC via CSN-associated USP15. The CSN regulates the balance between beta-catenin and APC. Disturbance of this balance can cause cancer by driving cell transformation, tumour angiogenesis and metastasis. A model is provided that proposes a role of CSN-mediated deneddylation in the formation of the beta-catenin-degrading supercomplex and the protection of complex-bound A-PC via CSN-associated USP15. (C) 2009 Elsevier Ltd. All rights reserved.