CHIP deletion reveals functional redundancy of E3 ligases in promoting degradation of both signaling proteins and expanded glutamine proteins.
CHIP deletion reveals functional redundancy of E3 ligases in promoting degradation of both signaling proteins and expanded glutamine proteins.
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CHIP缺失揭示了E3连接酶在促进信号蛋白和扩展的谷氨酰胺蛋白的降解方面的功能冗余。
DOI：
10.1093/hmg/ddn296
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发表时间：
2008-12-15
影响因子：
3.5
通讯作者：
Lieberman AP
中科院分区：
文献类型：
--
作者：
Morishima Y;Wang AM;Yu Z;Pratt WB;Osawa Y;Lieberman AP
CHIP是一种E3泛素连接酶，与Hsp 70和Hsp 90结合，促进几种Hsp 90调节的信号蛋白和含有扩展的谷氨酰胺片段的致病蛋白的降解。在多聚谷氨酰胺疾病模型中，CHIP被认为是通过促进这些错误折叠的蛋白质的降解的主要保护因子。在这里，我们表明，两个CHIP底物，糖皮质激素受体（GR），一个经典的热休克蛋白90调节的信号蛋白，和扩展的谷氨酰胺雄激素受体（AR 112 Q），在CHIP-/-和CHIP+/+小鼠胚胎成纤维细胞与热休克蛋白90抑制剂格尔德霉素处理后，以相同的速度降解。CHIP−/−胞质溶胶具有与CHIP+/+胞质溶胶相同的能力，能够泛素化纯化的神经元型一氧化氮合酶（nNOS），另一种已建立的CHIP底物。为了确定与Hsp 70（Parkin）或Hsp 90（Mdm 2）结合的其他E3泛素连接酶是否作用于CHIP底物，将每种E3连接酶与GR、nNOS、AR 112 Q或Q78共济失调蛋白-3共表达。CHIP降低了所有四种蛋白的水平，Parkin作用于nNOS和Q78共济失调蛋白-3，但不作用于类固醇受体，Mdm 2不影响任何共表达的蛋白。此外，CHIP和帕金共定位于细胞培养物和脊髓和延髓肌肉萎缩症的敲入小鼠模型中形成的扩增的谷氨酰胺AR的聚集体。这些观察结果表明，CHIP在调节Hsp 90客户端信号传导蛋白或扩展的谷氨酰胺道蛋白的周转中不起排他性作用，并表明Hsp 70依赖性E3连接酶Parkin在某些底物上对CHIP起冗余作用。
CHIP, an E3 ubiquitin ligase that binds to Hsp70 and Hsp90, promotes degradation of several Hsp90-regulated signaling proteins and disease-causing proteins containing expanded glutamine tracts. In polyglutamine disease models, CHIP has been considered a primary protection factor by promoting degradation of these misfolded proteins. Here we show that two CHIP substrates, the glucocorticoid receptor (GR), a classic Hsp90-regulated signaling protein, and the expanded glutamine androgen receptor (AR112Q), are degraded at the same rate in CHIP−/− and CHIP+/+ mouse embryonic fibroblasts after treatment with the Hsp90 inhibitor geldanamycin. CHIP−/− cytosol has the same ability as CHIP+/+ cytosol to ubiquitylate purified neuronal nitric oxide synthase (nNOS), another established CHIP substrate. To determine if other E3 ubiquitin ligases that bind to Hsp70 (Parkin) or Hsp90 (Mdm2) act on CHIP substrates, each E3 ligase was co-expressed with the GR, nNOS, AR112Q or Q78 ataxin-3. CHIP lowered the levels of all four proteins, Parkin acted on nNOS and Q78 ataxin-3 but not on the steroid receptors, and Mdm2 did not affect any of the co-expressed proteins. Moreover, both CHIP and Parkin co-localized to aggregates of the expanded glutamine AR formed in cell culture and in a knock-in mouse model of spinal and bulbar muscular atrophy. These observations establish that CHIP does not play an exclusive role in regulating the turnover of Hsp90 client signaling proteins or expanded glutamine tract proteins, and show that the Hsp70-dependent E3 ligase Parkin acts redundantly to CHIP on some substrates.
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影响因子：
50.3
作者：
Isaacs, JS;Xu, WP;Neckers, L
通讯作者：
Neckers, L
影响因子：
2.1
作者：
Hatakeyama, S;Matsumoto, M;Nakayama, KI
通讯作者：
Nakayama, KI
影响因子：
21.3
作者：
Connell, P;Ballinger, CA;Patterson, C
通讯作者：
Patterson, C
影响因子：
4.8
作者：
Jiang, JH;Ballinger, CA;Patterson, C
通讯作者：
Patterson, C
影响因子：
5.6
作者：
Burch, L;Shimizu, H;Hupp, TR
通讯作者：
Hupp, TR