Distinct Roles for the Hsp40 and Hsp90 Molecular Chaperones during Cystic Fibrosis Transmembrane Conductance Regulator Degradation in Yeast
10.1091/mbc.e04-07-0584
Crossref journal-article
American Society for Cell Biology (ASCB)
Molecular Biology of the Cell (1076)
Abstract

Aberrant secreted proteins can be destroyed by ER-associated protein degradation (ERAD), and a prominent, medically relevant ERAD substrate is the cystic fibrosis transmembrane conductance regulator (CFTR). To better define the chaperone requirements during CFTR maturation, the protein was expressed in yeast. Because Hsp70 function impacts CFTR biogenesis in yeast and mammals, we first sought ER-associated Hsp40 cochaperones involved in CFTR maturation. Ydj1p and Hlj1p enhanced Hsp70 ATP hydrolysis but CFTR degradation was slowed only in yeast mutated for both YDJ1 and HLJ1, suggesting functional redundancy. In contrast, CFTR degradation was accelerated in an Hsp90 mutant strain, suggesting that Hsp90 preserves CFTR in a folded state, and consistent with this hypothesis, Hsp90 maintained the solubility of an aggregation-prone domain (NBD1) in CFTR. Soluble ERAD substrate degradation was unaffected in the Hsp90 or the Ydj1p/Hlj1p mutants, and surprisingly CFTR degradation was unaffected in yeast mutated for Hsp90 cochaperones. These results indicate that Hsp90, but not the Hsp90 complex, maintains CFTR structural integrity, whereas Ydj1p/Hlj1p catalyze CFTR degradation.

Bibliography

Youker, R. T., Walsh, P., Beilharz, T., Lithgow, T., & Brodsky, J. L. (2004). Distinct Roles for the Hsp40 and Hsp90 Molecular Chaperones during Cystic Fibrosis Transmembrane Conductance Regulator Degradation in Yeast. Molecular Biology of the Cell, 15(11), 4787–4797.

Authors 5
  1. Robert T. Youker (first)
  2. Peter Walsh (additional)
  3. Traude Beilharz (additional)
  4. Trevor Lithgow (additional)
  5. Jeffrey L. Brodsky (additional)
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Dates
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Created 21 years ago (Sept. 2, 2004, 3:20 a.m.)
Deposited 4 years, 2 months ago (June 25, 2021, 7:54 a.m.)
Indexed 3 months, 2 weeks ago (May 16, 2025, 6:04 a.m.)
Issued 20 years, 10 months ago (Nov. 1, 2004)
Published 20 years, 10 months ago (Nov. 1, 2004)
Published Print 20 years, 10 months ago (Nov. 1, 2004)
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@article{Youker_2004, title={Distinct Roles for the Hsp40 and Hsp90 Molecular Chaperones during Cystic Fibrosis Transmembrane Conductance Regulator Degradation in Yeast}, volume={15}, ISSN={1939-4586}, url={http://dx.doi.org/10.1091/mbc.e04-07-0584}, DOI={10.1091/mbc.e04-07-0584}, number={11}, journal={Molecular Biology of the Cell}, publisher={American Society for Cell Biology (ASCB)}, author={Youker, Robert T. and Walsh, Peter and Beilharz, Traude and Lithgow, Trevor and Brodsky, Jeffrey L.}, year={2004}, month=nov, pages={4787–4797} }