期刊
CELL
卷 127, 期 4, 页码 803-815出版社
CELL PRESS
DOI: 10.1016/j.cell.2006.09.043
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资金
- NCRR NIH HHS [RR11823] Funding Source: Medline
- NHLBI NIH HHS [R01 HL079442] Funding Source: Medline
- NIDDK NIH HHS [DK51870] Funding Source: Medline
- NIGMS NIH HHS [GM78654, GM45678, GM42336] Funding Source: Medline
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.
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