Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis.
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.
Mesh Terms:
Animals, Cricetinae, Cystic Fibrosis, Cystic Fibrosis Transmembrane Conductance Regulator, Down-Regulation, Electric Conductivity, Endoplasmic Reticulum, HSP90 Heat-Shock Proteins, Humans, Iodides, Molecular Chaperones, Mutant Proteins, Protein Binding, Protein Folding, Protein Transport, Proteome, RNA, Small Interfering, Thermodynamics
Animals, Cricetinae, Cystic Fibrosis, Cystic Fibrosis Transmembrane Conductance Regulator, Down-Regulation, Electric Conductivity, Endoplasmic Reticulum, HSP90 Heat-Shock Proteins, Humans, Iodides, Molecular Chaperones, Mutant Proteins, Protein Binding, Protein Folding, Protein Transport, Proteome, RNA, Small Interfering, Thermodynamics
Cell
Date: Nov. 17, 2006
PubMed ID: 17110338
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