The co-chaperone CHIP regulates protein triage decisions mediated by heat-shock proteins
The co-chaperone CHIP regulates protein triage decisions mediated by heat-shock proteins
复制标题
DOI：
10.1038/35050618
复制
发表时间：
2001-01-01
影响因子：
21.3
通讯作者：
Patterson, C
中科院分区：
文献类型：
--
作者：
Connell, P;Ballinger, CA;Patterson, C
为了维持细胞中的质量控制，机制区分不正确折叠的肽、成熟和功能性蛋白质以及待靶向降解的蛋白质。分子伴侣，包括热休克蛋白Hsp 90，具有识别错误折叠的蛋白质并帮助其转化为功能构象的能力。Hsp 90抑制剂格尔德霉素对Hsp 90杂合物的破坏导致底物通过泛素-蛋白酶体途径降解（1-3），表明该系统参与蛋白质分类决策。我们先前鉴定了CHIP（Hsc 70相互作用蛋白的羧基末端）是Hsc 70的相互作用伴侣（参考文献4）。CHIP还直接与热休克蛋白90的一个三联肽重复受体位点相互作用，掺入热休克蛋白90杂合物中并引发调节辅因子p23的释放。在这里，我们发现CHIP消除了糖皮质激素受体的类固醇结合活性和反式激活潜力，糖皮质激素受体是一种充分表征的Hsp 90底物（5），即使它对它的合成几乎没有影响。相反，CHIP诱导糖皮质激素受体的泛素化和通过蛋白酶体降解。通过重塑热休克蛋白90杂合物，有利于底物降解，CHIP调制蛋白质分类决策，调节蛋白质折叠和伴侣底物降解之间的平衡。
To maintain quality control in cells, mechanisms distinguish among improperly folded peptides, mature and functional proteins, and proteins to be targeted for degradation. The molecular chaperones, including heat-shock protein Hsp90, have the ability to recognize misfolded proteins and assist in their conversion to a functional conformation. Disruption of Hsp90 heterocomplexes by the Hsp90 inhibitor geldanamycin leads to substrate degradation through the ubiquitin-proteasome pathway(1-3), implicating this system in protein triage decisions. We previously identified CHIP (carboxyl terminus of Hsc70-interacting protein) to be an interaction partner of Hsc70 (ref. 4). CHIP also interacts directly with a tetratricopeptide repeat acceptor site of Hsp90, incorporating into Hsp90 heterocomplexes and eliciting release of the regulatory cofactor p23. Here we show that CHIP abolishes the steroid-binding activity and transactivation potential of the glucocorticoid receptor, a well-characterized Hsp90 substrate(5), even though it has little effect on its synthesis. Instead, CHIP induces ubiquitylation of the glucocorticoid receptor and degradation through the proteasome. By remodelling Hsp90 heterocomplexes to favour substrate degradation, CHIP modulates protein triage decisions that regulate the balance between protein folding and degradation for chaperone substrates.