Mutant huntingtin represses CBP, but not p300, by binding and protein degradation
Mutant huntingtin represses CBP, but not p300, by binding and protein degradation
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DOI：
10.1016/j.mcn.2005.10.015
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发表时间：
2005-12-01
影响因子：
3.5
通讯作者：
Dorsman, JC
中科院分区：
文献类型：
--
作者：
Cong, SY;Pepers, BA;Dorsman, JC
亨廷顿舞蹈病可用作研究由易聚集蛋白引起的神经退行性疾病的模型。有人提出，转录因子在聚集体中的捕获在发病机制中起着重要作用。我们现在报道，CBP 的转录活性在早期时间点已被可溶性突变亨廷顿蛋白抑制，而 CBP/p300 的组蛋白乙酰化酶活性随着时间的推移逐渐减弱。突变亨廷顿蛋白与 CBP 的结合比正常亨廷顿蛋白强得多，这可能有助于抑制。特别是在后来的时间点，CBP蛋白水平通过蛋白酶体途径逐渐降低。与此形成鲜明对比的是，p300 不受突变亨廷顿蛋白的影响。这种 CBP 的选择性降解在脊髓小脑共济失调 3 中不存在。因此，突变型亨廷顿蛋白在早期和晚期时间点通过多种机制特异性影响 CBP 而不是 p300。除了 CBP 的减少外，这些密切相关的组蛋白乙酰转移酶的比例改变也可能影响染色质结构和转录，从而导致神经退行性变。 (c) 2005 Elsevier Inc. 保留所有权利。
Huntington's disease can be used as a model to study neurodegenerative disorders caused by aggregation-prone proteins. It has been proposed that the entrapment of transcription factors in aggregates plays an important role in pathogenesis. We now report that the transcriptional activity of CBP is already repressed in the early time points by soluble mutant huntingtin, whereas the histone acetylase activity of CBP/p300 is gradually diminished over time. Mutant huntingtin bound much stronger to CBP than normal huntingtin, possibly contributing to repression. Especially at the later time points, CBP protein level was gradually reduced via the proteasome pathway. In sharp contrast, p300 was unaffected by mutant huntingtin. This selective degradation of CBP was absent in spinocerebellar ataxia 3. Thus, mutant huntingtin specifically affects CBP and not p300 both at the early and later time points, via multiple mechanisms. In addition to the reduction of CBP, also the altered ratio of these closely related histone acetyltransferases may affect chromatin structure and transcription and thus contribute to neurodegeneration. (c) 2005 Elsevier Inc. All rights reserved.