Polyglutamine-expanded androgen receptors form aggregates that sequester heat shock proteins, proteasome components and SRC-1, and are suppressed by the HDJ-2 chaperone
Polyglutamine-expanded androgen receptors form aggregates that sequester heat shock proteins, proteasome components and SRC-1, and are suppressed by the HDJ-2 chaperone
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DOI：
10.1093/hmg/8.5.731
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发表时间：
1999-05-01
影响因子：
3.5
通讯作者：
Mancini, MA
中科院分区：
文献类型：
--
作者：
Stenoien, DL;Cummings, CJ;Mancini, MA
脊髓延髓肌萎缩症是一种神经退行性疾病，由雄激素受体（AR）中的多聚谷氨酰胺扩增引起。我们表明，在瞬时转染的HeLa细胞中，AR含有48个谷氨酰胺（ARQ 48）积累在细胞质和核聚集体中的依赖性的方式。电子显微镜显示两种类型的聚集体具有相似的超微结构。ARQ 48聚集体隔离线粒体和类固醇受体共激活因子1，并对NEDD 8、Hsp 70、Hsp 90和HDJ-2/HSDJ染色呈阳性。HDJ-2/HSDJ的共表达显著抑制聚集体形成。ARQ 48聚集体还标记有识别PA 700蛋白酶体帽而不是20 S核心颗粒的抗体。这些结果表明，ARQ 48由于蛋白质错误折叠和蛋白水解加工中的分解而积累。此外，与聚集体形成相关的稳态紊乱可能影响正常细胞功能。
Spinal bulbar muscular atrophy is a neurodegenerative disorder caused by a polyglutamine expansion in the androgen receptor (AR). We show in transiently transfected HeLa cells that an AR containing 48 glutamines (ARQ48) accumulates in a hormone-dependent manner in both cytoplasmic and nuclear aggregates. Electron microscopy reveals both types of aggregates to have a similar ultrastructure. ARQ48 aggregates sequester mitochondria and steroid receptor coactivator 1 and stain positively for NEDD8, Hsp70, Hsp90 and HDJ-2/HSDJ. Co-expression of HDJ-2/HSDJ significantly represses aggregate formation. ARQ48 aggregates also label with antibodies recognizing the PA700 proteasome caps but not 20S core particles, These results suggest that ARQ48 accumulates due to protein misfolding and a breakdown in proteolytic processing, Furthermore, the homeostatic disturbances associated with aggregate formation may affect normal cell function.