Molecular clearance of ataxin-3 is regulated by a mammalian E4
Molecular clearance of ataxin-3 is regulated by a mammalian E4
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DOI：
10.1038/sj.emboj.7600081
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发表时间：
2004-02-11
期刊：
影响因子：
11.4
通讯作者：
Nakayama, KI
中科院分区：
文献类型：
--
作者：
Matsumoto, M;Yada, M;Nakayama, KI
含有多聚谷氨酰胺的蛋白质的不溶性聚集体通常与患有多聚谷氨酰胺疾病的个体的神经元中的泛素缀合。我们现在表明，ataxin-3（其中多聚谷氨酰胺束的异常扩张导致脊髓小脑共济失调 3 型（SCA3））经历了蛋白酶体的泛素化和降解。哺乳动物 E4B (UFD2a) 是一种泛素链组装因子 (E4)，与 ataxin-3 的多泛素化活性共纯化。 E4B 与 ataxin-3 相互作用，从而介导其多泛素化。 E4B 的表达促进了 ataxin-3 病理形式的降解。相比之下，E4B 的显性失活突变体抑制这种形式的 ataxin-3 的降解，导致细胞内聚集体的形成。在 SCA3 果蝇模型中，E4B 的表达抑制了 ataxin-3 突变体诱导的神经变性。这些观察结果表明，E4 是 ataxin-3 病理形式降解的限速因素，并且 E4B 的靶向表达是 SCA3 的潜在基因疗法。
Insoluble aggregates of polyglutamine-containing proteins are usually conjugated with ubiquitin in neurons of individuals with polyglutamine diseases. We now show that ataxin-3, in which the abnormal expansion of a polyglutamine tract is responsible for spinocerebellar ataxia type 3 (SCA3), undergoes ubiquitylation and degradation by the proteasome. Mammalian E4B (UFD2a), a ubiquitin chain assembly factor (E4), copurified with the polyubiquitylation activity for ataxin-3. E4B interacted with, and thereby mediated polyubiquitylation of, ataxin-3. Expression of E4B promoted degradation of a pathological form of ataxin-3. In contrast, a dominant-negative mutant of E4B inhibited degradation of this form of ataxin-3, resulting in the formation of intracellular aggregates. In a Drosophila model of SCA3, expression of E4B suppressed the neurodegeneration induced by an ataxin-3 mutant. These observations suggest that E4 is a rate-limiting factor in the degradation of pathological forms of ataxin-3, and that targeted expression of E4B is a potential gene therapy for SCA3.