X-linked intellectual disability gene CUL4B targets Jab1/CSN5 for degradation and regulates bone morphogenetic protein signaling
X-linked intellectual disability gene CUL4B targets Jab1/CSN5 for degradation and regulates bone morphogenetic protein signaling
复制标题
X 连锁智力障碍基因 CUL4B 以 Jab1/CSN5 为目标进行降解并调节骨形态发生蛋白信号传导。
DOI：
10.1016/j.bbadis.2013.01.015
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发表时间：
2013-05-01
影响因子：
6.2
通讯作者：
Gong, Yaoqin
中科院分区：
文献类型：
--
作者：
He, Fengjuan;Lu, Defen;Gong, Yaoqin
Cullin 4 B（CUL 4 B）是一种参与Cullin-RING泛素连接酶（E3）复合物组装的支架蛋白。当代的报道已经确定CUL 4 B基因的多个突变与X连锁智力残疾（XLID）有因果关系。确定特异性蛋白底物将有助于更好地理解CUL 4 B的生理功能。目前的研究将COP 9信号体（CSN）复合物中的Jun激活结构域结合蛋白（Jab 1/CSN 5）鉴定为CUL 4 B泛素连接酶复合物的新型蛋白水解靶标。在RNAi介导的CUL 4 B耗竭后，在细胞中观察到Jab 1的降解受损。DDB 1-CUL 4 B-ROC 1的完整性进一步证明对于Jab 1的降解是必不可少的。此外，Jab 1的降解不依赖于CUL 4A，CUL 4A是与CUL 4 B密切相关的cullin家族成员。体外和体内泛素化实验表明，CUL 4 B促进Jab 1的多聚泛素化。有趣的是，CUL 4 B沉默的细胞显示出骨形态发生蛋白（BMP）信号传导的异常上调。此外，Cul 4 b缺陷小鼠胚胎成纤维细胞的体内研究表明Jab 1积累和BMP信号通路的激活增加。总之，目前的研究结果表明，CUL 4 B E3泛素连接酶在靶向Jab 1降解中起着关键作用，可能揭示了以前未记录的与基于CUL 4 B的E3复合物相关的BMP信号通路调节机制。这一观察结果可能提供新的见解CUL 4 B相关XLID发病机制的分子机制。(C)2013爱思唯尔有限公司版权所有。
Cullin 4B (CUL4B) is a scaffold protein involved in the assembly of cullin-RING ubiquitin ligase (E3) complexes. Contemporary reports have identified multiple mutations of CUL4B gene as being causally associated with X-linked intellectual disability (XLID). Identifying the specific protein substrates will help to better understand the physiological functions of CUL4B. The current study identified Jun activation domain-binding protein (Jab1/CSN5) in the COP9 signalosome (CSN) complex as a novel proteolytic target for the CUL4B ubiquitin ligase complex. The impaired degradation of Jab1 was observed in cells after RNAi-mediated CUL4B depletion. Integrity of DDB1-CUL4B-ROC1 was further demonstrated to be indispensable for the degradation of Jab1. In addition, the degradation of Jab1 is independent of CUL4A, a cullin family member closely related to CUL4B. In vitro and in vivo ubiquitination assays revealed that CUL4B promoted the polyubiquitination of Jab1. Interestingly, CUL4B-silenced cells were shown to exhibit abnormal upregulation of bone morphogenetic protein (BMP) signaling. Furthermore, in vivo studies of embryonic fibroblasts in Cul4b-deficient mice demonstrated Jab1 accumulation and increased activation of the BMP signaling pathway. Together, the current findings demonstrate the CUL4B E3 ubiquitin ligase plays a key role in targeting Jab1 for degradation, potentially revealing a previously undocumented mechanism for regulation of the BMP signaling pathway involved with the CUL4B-based E3 complex. This observation may provide novel insights into the molecular mechanisms underlying CUL4B-associated XLID pathogenesis. (C) 2013 Elsevier B.V. All rights reserved.