COP9 limits dendritic branching via Cullin3-dependent degradation of the actin-crosslinking BTB-domain protein Kelch.
COP9 limits dendritic branching via Cullin3-dependent degradation of the actin-crosslinking BTB-domain protein Kelch.
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DOI：
10.1371/journal.pone.0007598
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发表时间：
2009-10-27
期刊：
影响因子：
3.7
通讯作者：
Doronkin S
中科院分区：
文献类型：
--
作者：
Djagaeva I;Doronkin S
COP9信号体（CSN）是保守的26 S蛋白酶体降解途径的关键成员，已被检测到在几种衰弱综合征患者中发生改变。这些结果表明，CSN的行为在神经回路，但在大脑中的CSN的确切功能尚未确定。以前，使用果蝇外周神经系统（PNS）作为模型系统，我们确定，CSN是树突状形态发生的一个关键调节器。我们发现CSN的缺陷导致了显著的对比表型，即减少或刺激树突状分支。特别是，我们已经报道，CSN刺激树突状分支通过Cullin1介导的蛋白水解。在这里，我们描述了CSN通过控制Cullin 3功能抑制PNS神经元中的树突分支：Cullin 3的缺失导致过度的树突分支。我们还确定了神经元中Cullin3依赖性降解的下游靶点-肌动蛋白交联BTB结构域蛋白Kelch。不适当的积累Kelch，无论是由于受损的Cullin3依赖性营业额，或异位表达Kelch，导致不受控制的树突状分支。这些发现表明，CSN通路以多层方式调节神经元网络，为CSN在人类精神发育迟滞疾病和神经退行性疾病中的作用提供了新的见解。
Components of the COP9 signalosome (CSN), a key member of the conserved 26S proteasome degradation pathway, have been detected to be altered in patients of several debilitating syndromes. These findings suggest that CSN acts in neural circuits, but the exact function of CSN in brain remains unidentified. Previously, using Drosophila peripheral nervous system (PNS) as a model system, we determined that CSN is a critical regulator of dendritic morphogenesis. We found that defects in CSN led to the strikingly contrast phenotype of either reducing or stimulating dendritic branching. In particular, we have reported that CSN stimulates dendritic branching via Cullin1-mediated proteolysis. Here we describe that CSN inhibits dendritic arborization in PNS neurons acting via control of Cullin3 function: loss of Cullin3 causes excessive dendritic branching. We also identified a downstream target for Cullin3-dependent degradation in neurons – the actin-crosslinking BTB-domain protein Kelch. Inappropriate accumulation of Kelch, either due to the impaired Cullin3-dependent turnover, or ectopic expression of Kelch, leads to uncontrolled dendritic branching. These findings indicate that the CSN pathway modulates neuronal network in a multilayer manner, providing the foundation for new insight into the CSN role in human mental retardation disorders and neurodegenerative disease.