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MBC in Press, published online ahead of print September 1, 2004
Mol. Biol. Cell 10.1091/mbc.E04-07-0584

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Submitted on July 13, 2004
Revised on August 4, 2004
Accepted on August 19, 2004

Distinct Roles for the Hsp40 and Hsp90 Molecular Chaperones during Cystic Fibrosis Transmembrane Conductance Regulator Degradation in Yeast

Robert T. Youker,* Peter Walsh,{dagger} Traude Beilharz,{dagger} Trevor Lithgow,{dagger} and Jeffrey L. Brodsky*{ddagger}

*Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA; {dagger}Russell Grimwade School of Biochemistry & Molecular Biology, University of Melbourne, Parkville 3010, Australia

Monitoring Editor: Reid Gilmore

Aberrant secreted proteins can be destroyed by ER associated protein degradation (ERAD), and a prominent, medically-relevant ERAD substrate is 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.

{ddagger}Corresponding author. E-mail: jbrodsky{at}pitt.edu






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