Huntingtin-associated protein 1 (HAP1) interacts with androgen receptor (AR) and suppresses SBMA-mutant-AR-induced apoptosis.
Huntingtin-associated protein 1 (HAP1) interacts with androgen receptor (AR) and suppresses SBMA-mutant-AR-induced apoptosis.
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DOI：
10.1093/hmg/ddl156
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发表时间：
2006-08
影响因子：
3.5
通讯作者：
Y. Takeshita;Ryutaro Fujinaga;Changjiu Zhao;Akie Yanai;K. Shinoda
中科院分区：
文献类型：
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作者：
Y. Takeshita;Ryutaro Fujinaga;Changjiu Zhao;Akie Yanai;K. Shinoda
亨廷顿蛋白相关蛋白1（Huntingtin associated protein 1，HAP 1）是亨廷顿蛋白的相互作用蛋白，是豆状体（stigmoid body，STB）的重要组成部分，近年来研究发现HAP 1对亨廷顿病（Huntington 'sdisease，HD）的神经退行性变具有保护作用。在本研究中，HAP 1和雄激素受体（AR）与一个长的聚谷氨酰胺束（polyQ）来自脊髓和延髓肌肉萎缩症（SBMA）的亚细胞之间的联系进行了检查使用HEp-2细胞与HAP 1和/或正常ARQ 25，SBMA突变ARQ 65或缺失突变AR cDNA共转染。结果提供了第一个明确的证据，即HAP 1通过其配体结合结构域以polyQ长度依赖性方式与AR相互作用，并形成突出的包含物隔离polyQ-AR，并且添加双氢睾酮降低HAP 1与ARQ 25的缔合强度比与ARQ 65的缔合强度更显著。此外，SBMA突变体ARQ 65诱导的细胞凋亡被HAP 1共转染抑制。我们的研究结果强烈表明，HAP 1/STB是相关的polyQ长度依赖性修饰亚细胞AR功能，并参与发病机制，不仅HD，但也SBMA作为一个重要的内在神经保护剂确定细胞凋亡的阈值脆弱性。结合先前的报道，HAP 1/STB选择性地在HD和SBMA中免于退行性靶点的脑区域中表达，目前的研究可能解释这两种疾病中神经退行性变的区域特异性发生，揭示其分子病理机制的共同方面以及尚未发现的HD和SBMA患者的诊断或治疗应用。
Huntingtin-associated protein 1 (HAP1), an interactor of huntingtin, has been known as an essential component of the stigmoid body (STB) and recently reported to play a protective role against neurodegeneration in Huntington's disease (HD). In the present study, subcellular association between HAP1 and androgen receptor (AR) with a long polyglutamine tract (polyQ) derived from spinal-and-bulbar-muscular-atrophy (SBMA) was examined using HEp-2 cells cotransfected with HAP1 and/or normal ARQ25, SBMA-mutant ARQ65 or deletion-mutant AR cDNAs. The results provided the first clear evidence that HAP1 interacts with AR through its ligand-binding domain in a polyQ-length-dependent manner and forms prominent inclusions sequestering polyQ-AR, and that addition of dihydrotestosterone reduces the association strength of HAP1 with ARQ25 more dramatically than that with ARQ65. Furthermore, SBMA-mutant-ARQ65-induced apoptosis was suppressed by cotransfection with HAP1. Our findings strongly suggest that HAP1/STB is relevant to polyQ-length-dependent modification on subcellular AR functions and critically involved in pathogenesis of not only HD but also SBMA as an important intrinsic neuroprotectant determining the threshold for cellular vulnerability to apoptosis. Taking together with previous reports that HAP1/STB is selectively expressed in the brain regions spared from degenerative targets in HD and SBMA, the current study might explain the region-specific occurrence of neurodegeneration in both diseases, shedding light on common aspects of their molecular pathological mechanism and yet-to-be-uncovered diagnostic or therapeutic applications for HD and SBMA patients.