BimEL as a possible molecular link between proteasome dysfunction and cell death induced by mutant huntingtin.
BimEL as a possible molecular link between proteasome dysfunction and cell death induced by mutant huntingtin.
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DOI：
10.1111/j.1460-9568.2010.07215.x
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发表时间：
2010-06
期刊：
影响因子：
--
通讯作者：
Wei J
中科院分区：
文献类型：
--
作者：
Leon R;Bhagavatula N;Ulukpo O;McCollum M;Wei J
亨廷顿氏病（HD）是由亨廷顿蛋白N-末端内的多聚谷氨酰胺重复序列扩增引起的破坏性神经退行性疾病。其特征在于纹状体中的中型多刺神经元的选择性损失。研究表明，蛋白酶体功能受损和内质网应激在突变型亨廷顿蛋白（mHtt）诱导的细胞死亡中起重要作用。然而，所涉及的分子连接知之甚少。在本研究中，我们确定了超长形式的Bim（Bcl-2相互作用的细胞死亡介质），BimEL，在mHtt诱导的细胞死亡的重要作用。在表达mHtt的N-末端的细胞系和HD小鼠模型中，BimEL蛋白表达水平显著增加。虽然定量RT-PCR分析表明，在表达mHtt的细胞中，BimEL mRNA增加，我们提供的证据表明，在翻译后水平，BimEL的磷酸化在调节BimEL表达中起着更重要的作用。BimEL的上调促进Bax易位到线粒体膜，这进一步导致细胞色素c的释放和细胞死亡。另一方面，敲低BimEL表达阻止mHtt诱导的细胞死亡。综上所述，这些发现表明，BimEL是调节mHtt诱导的细胞死亡的关键因素。提出了描述BimEL在连接mHtt诱导的ER应激和蛋白酶体功能障碍与细胞死亡中的作用的模型。
Huntington’s disease (HD) is a devastating neurodegenerative disorder caused by an expanded polyglutamine repeat within the N-terminus of the huntingtin protein. It is characterized by a selective loss of medium spiny neurons in the striatum. It has been suggested that impaired proteasome function and ER stress play important roles in mutant huntingtin (mHtt) induced cell death. However, the molecular link involved is poorly understood. In the present study, we identified the essential role of the extra long form of Bim (Bcl-2 interacting mediator of cell death), BimEL, in mHtt-induced cell death. BimEL protein expression level was significantly increased in cell lines expressing the N-terminus of mHtt and in a mouse model of HD. Although quantitative RT-PCR analysis indicated that BimEL mRNA was increased in cells expressing mHtt, we provided evidence showing that, at the post-translational level, phosphorylation of BimEL played a more important role in regulating BimEL expression. Up-regulation of BimEL facilitated the translocation of Bax to the mitochondrial membrane, which further led to cytochrome c release and cell death. On the other hand, knocking down BimEL expression prevented mHtt-induced cell death. Taken together, these findings suggest that BimEL is a key element in regulating mHtt-induced cell death. A model depicting the role of BimEL in linking mHtt-induced ER stress and proteasome dysfunction to cell death is proposed.
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