Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis.

By Xiaodong Wang, John D. Venable, P. LaPointe, D. Hutt, Atanas V. Koulov, J. Coppinger, C. Gurkan, Wendy A. Kellner, J. Matteson, H. Plutner and 4 more. Cell, 2006

622 citations recorded by the source corpus.

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.

Subfields: Cell Biology, Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/2327b8b72e3ae1df0d2208f996870acd90ede6ff

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In Cell Biology

1. Richard I. Morimoto
2. Susan Lindquist
3. Jie Zheng
4. M. Trudeau
5. F. Hartl

In Molecular Biology

1. Richard I. Morimoto
2. Susan Lindquist
3. Mikko Taipale
4. Jie Zheng
5. M. Trudeau
6. F. Hartl
7. M. Hayer-Hartl
8. Christopher M. Dobson

Citations in the corpus

• Handbook of ion channels (2015, background): “Finally, the mature, fully glycosylated, CFTR complex enters the secretory system via coat protein complex II (COPII) transport vesicles from the Golgi apparatus (Wang et al., 2006; Younger et al., 2006).”
• Proteotoxic stress and inducible chaperone networks in neurodegenerative disease and aging. (2008, background): “For example, altering the levels of Aha1, a cochaperone of Hsp90, corrects the folding and trafficking of mutant CFTR (Wang et al. 2006).”
• HSP90 at the hub of protein homeostasis: emerging mechanistic insights (2010, background): “As just one example relevant to human disease, the maturation defect of the cystic fibrosis-associated mutant protein CFTRdel508, an HSP90 client, can be reversed by depletion of the co-chaperone AHA1 (Ref”