Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis
Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis
复制标题
DOI：
10.1016/j.cell.2006.09.043
复制
发表时间：
2006-11-17
期刊：
影响因子：
64.5
通讯作者：
Balch, William E.
中科院分区：
文献类型：
--
作者：
Wang, Xiaodong;Venable, John;Balch, William E.
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Delta F508的细胞表面拯救可以通过Hsp90辅伴侣ATP酶调节剂Aha1的部分siRNA沉默来启动。我们认为Delta F508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。
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, Delta F508, can be initiated by partial siRNA silencing of the Hsp90 cochaperone ATPase regulator Aha1. We propose that failure of Delta F508 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.