NEDL1, a novel ubiquitin-protein isopeptide ligase for dishevelled-1, targets mutant superoxide dismutase-1
NEDL1, a novel ubiquitin-protein isopeptide ligase for dishevelled-1, targets mutant superoxide dismutase-1
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DOI：
10.1074/jbc.m312389200
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发表时间：
2004-03-19
影响因子：
4.8
通讯作者：
Nakagawara, A
中科院分区：
文献类型：
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作者：
Miyazaki, K;Fujita, T;Nakagawara, A
大约20%的家族性肌萎缩性侧索硬化症（FALS）源于超氧化物歧化酶-1（SOD 1）基因的种系突变。然而，该过程的分子机制一直难以捉摸。在这里，我们表明，神经元同源E6 AP羧基末端（HECT）型泛素蛋白异肽连接酶（NEDL 1）物理上结合translocon相关蛋白-δ，也结合和泛素化突变体（但不是野生型）SOD 1 proportionarly由该特定突变体引起的疾病的严重程度。免疫组化结果显示，NEDL 1蛋白存在于FALS患者和突变型SOD 1转基因小鼠脊髓腹角运动神经元的路易小体样透明包涵体的中心区域。双杂交筛选NEDL 1的生理靶点已经确定了Dishevelled-1，这是Wnt信号通路中的关键转导子之一。突变SOD 1也与Dishevelled-1在NEDL 1的存在下相互作用，并导致其功能障碍。因此，我们的研究结果表明，错误折叠的SOD 1，NEDL 1，translocon相关蛋白-delta和Dishevelled-1之间的不良相互作用形成了一种泛素化蛋白复合物，该复合物包含在潜在的细胞毒性蛋白聚集体中，并相互影响其功能，导致FALS中的运动神经元死亡。
Approximately 20% of familial amyotrophic lateral sclerosis (FALS) arises from germ-line mutations in the superoxide dismutase-1 (SOD1) gene. However, the molecular mechanisms underlying the process have been elusive. Here, we show that a neuronal homologous to E6AP carboxyl terminus (HECT)-type ubiquitin-protein isopeptide ligase (NEDL1) physically binds translocon-associated protein-delta and also binds and ubiquitinates mutant (but not wild-type) SOD1 proportionately to the disease severity caused by that particular mutant. Immunohistochemically, NEDL1 is present in the central region of the Lewy body-like hyaline inclusions in the spinal cord ventral horn motor neurons of both FALS patients and mutant SOD1 transgenic mice. Two-hybrid screening for the physiological targets of NEDL1 has identified Dishevelled-1, one of the key transducers in the Wnt signaling pathway. Mutant SOD1 also interacted with Dishevelled-1 in the presence of NEDL1 and caused its dysfunction. Thus, our results suggest that an adverse interaction among misfolded SOD1, NEDL1, translocon-associated protein-delta, and Dishevelled-1 forms a ubiquitinated protein complex that is included in potentially cytotoxic protein aggregates and that mutually affects their functions, leading to motor neuron death in FALS.