A novel brain-enriched E3 ubiquitin ligase RNF182 is up regulated in the brains of Alzheimer's patients and targets ATP6V0C for degradation.
A novel brain-enriched E3 ubiquitin ligase RNF182 is up regulated in the brains of Alzheimer's patients and targets ATP6V0C for degradation.
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DOI：
10.1186/1750-1326-3-4
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发表时间：
2008-02-25
影响因子：
15.1
通讯作者：
Liu R
中科院分区：
文献类型：
--
作者：
Liu QY;Lei JX;Sikorska M;Liu R
多种细胞通路的改变会导致慢性神经退行性疾病的发生，例如散发性阿尔茨海默病 (AD)。这些反过来又涉及基因表达的变化，其中包括调节蛋白质加工和周转的基因，例如泛素-蛋白酶体系统的组成部分。最近，我们发现了一种 cDNA，其表达在 AD 大脑中发生了改变。它含有 247 个氨基酸的开放阅读框，代表一种新型环指蛋白 RNF182。在这里，我们检查了它的生化特性和在脑细胞中的假定作用。 RNF182 是一种低丰度细胞质蛋白，优先在大脑中表达。它的表达在死后 AD 脑组织中升高，并且在体外培养的遭受细胞死亡诱导损伤的神经元中，该基因的表达上调。随后，我们确定RNF182蛋白具有E3泛素连接酶活性，并在体外刺激E2依赖性多泛素化。酵母双杂交筛选、过表达和共沉淀方法在体外和体内均揭示了 RNF182 和 ATP6V0C 之间的相互作用，因其在间隙连接复合物和神经递质释放通道形成中的作用而闻名。数据表明，RNF182 通过泛素-蛋白酶体途径靶向 ATP6V0C 进行降解。 RNF182 的过度表达会降低细胞活力，而且该基因本身似乎可以破坏细胞稳态。综上所述，我们发现了一种新型的大脑富集环指 E3 连接酶，该酶在 AD 大脑和暴露于伤害性损伤的神经元细胞中表达上调。它与 ATP6V0C 蛋白相互作用，表明它可能在控制神经递质释放机制的重要组成部分的周转中发挥非常特殊的作用。
Alterations in multiple cellular pathways contribute to the development of chronic neurodegeneration such as a sporadic Alzheimer's disease (AD). These, in turn, involve changes in gene expression, amongst which are genes regulating protein processing and turnover such as the components of the ubiquitin-proteosome system. Recently, we have identified a cDNA whose expression was altered in AD brains. It contained an open reading frame of 247 amino acids and represented a novel RING finger protein, RNF182. Here we examined its biochemical properties and putative role in brain cells. RNF182 is a low abundance cytoplasmic protein expressed preferentially in the brain. Its expression was elevated in post-mortem AD brain tissue and the gene could be up regulated in vitro in cultured neurons subjected to cell death-inducing injuries. Subsequently, we have established that RNF182 protein possessed an E3 ubiquitin ligase activity and stimulated the E2-dependent polyubiquitination in vitro. Yeast two-hybrid screening, overexpression and co-precipitation approaches revealed, both in vitro and in vivo, an interaction between RNF182 and ATP6V0C, known for its role in the formation of gap junction complexes and neurotransmitter release channels. The data indicated that RNF182 targeted ATP6V0C for degradation by the ubiquitin-proteosome pathway. Overexpression of RNF182 reduced cell viability and it would appear that by itself the gene can disrupt cellular homeostasis. Taken together, we have identified a novel brain-enriched RING finger E3 ligase, which was up regulated in AD brains and neuronal cells exposed to injurious insults. It interacted with ATP6V0C protein suggesting that it may play a very specific role in controlling the turnover of an essential component of neurotransmitter release machinery.
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影响因子：
3.4
作者：
Niikura, T;Hashimoto, Y;Nishimoto, I
通讯作者：
Nishimoto, I
影响因子：
4.7
作者：
Sahara, N;Murayama, M;Takashima, A
通讯作者：
Takashima, A
影响因子：
3.5
作者：
Lee, SJ;Choi, JY;Kang, S
通讯作者：
Kang, S
影响因子：
3.8
作者：
GRAHAM, FL;SMILEY, J;NAIRN, R
通讯作者：
NAIRN, R
影响因子：
5.4
作者：
Boutell, C;Sadis, S;Everett, RD
通讯作者：
Everett, RD