HSP90 COCHAPERONE AHA1 DOWNREGULATION RESCUES MISFOLDING OF CFTR IN CYSTIC FIBRO

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 通过真核细胞的胞外(分泌)途径区分折叠和错误折叠的货物运输的途径尚不清楚。利用蛋白质组学研究全球囊性纤维化(CF)跨膜传导调节蛋白(CFTR)的相互作用，我们发现Hsp90辅伴侣调节内质网(ER)中CFTR蛋白折叠的Hsp90依赖的稳定性。对最常见的内质网疾病变异体DeltaF508的细胞表面拯救可以通过部分沉默Hsp90辅伴侣ATPase调节子Aha1来启动。我们认为，DeltaF508未能实现能量上有利的折叠，以响应伴侣折叠环境的稳态动力学(“分子伴侣”)，这是CF的病理生理机制之一。与货物相关的分子伴侣组分的活性可能是调节内质网退出折叠的常见机制，为纠正错误折叠疾病提供了一个一般框架。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The pathways that distinguish transport of folded and misfolded cargo through the exocytic (secretory) pathway of eukaryotic cells remain unknown. Using proteomics to assess global cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein interactions (the CFTR interactome), we show that Hsp90 cochaperones modulate Hsp90-dependent stability of CFTR protein folding in the endoplasmic reticulum (ER). Cell-surface rescue of the most common disease variant that is restricted to the ER, DeltaF508, can be initiated by partial siRNA silencing of the Hsp90 cochaperone ATPase regulator Aha1. We propose that failure of DeltaF508 to achieve an energetically favorable fold in response to the steady-state dynamics of the chaperone folding environment (the "chaperome") is responsible for the pathophysiology of CF. The activity of cargo-associated chaperome components may be a common mechanism regulating folding for ER exit, providing a general framework for correction of misfolding disease.