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的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 通过真核细胞的胞外（分泌）途径区分折叠和错误折叠货物的运输途径仍然未知。使用蛋白质组学评估全球囊性纤维化（CF）跨膜传导调节（CFTR）蛋白质的相互作用（CFTR相互作用组），我们表明，热休克蛋白90 cochaperones调节热休克蛋白90依赖的稳定性CFTR蛋白质折叠在内质网（ER）。限制于ER的最常见疾病变体DeltaF 508的细胞表面拯救可以通过Hsp 90辅伴侣ATP酶调节剂Aha 1的部分siRNA沉默来启动。我们提出，DeltaF 508未能响应分子伴侣折叠环境（“分子伴侣”）的稳态动力学而实现能量上有利的折叠是CF的病理生理学的原因。货物相关分子伴侣组成分的活性可能是调节ER退出折叠的常见机制，为纠正错误折叠疾病提供了一般框架。

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.