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MBC in Press, published online ahead of print December 20, 2006
Mol. Biol. Cell 10.1091/mbc.E06-05-0458

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Submitted on May 25, 2006
Revised on October 25, 2006
Accepted on December 5, 2006

Small Heat Shock Proteins Select {Delta}F508-CFTR for ER Associated Degradation (ERAD)

Annette Ahner,*{dagger} Kunio Nakatsukasa,* Hui Zhang,{dagger} Raymond A. Frizzell,{dagger} and Jeffrey L. Brodsky*

*Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260; {dagger}Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, PA 15261

Monitoring Editor: Jonathan Weissman

Secreted proteins that fail to achieve their native conformations, such as CFTR (Cystic Fibrosis Transmembrane conductance Regulator) and particularly the {Delta}F508-CFTR variant can be selected for ER-associated degradation (ERAD) by molecular chaperones. Because the message corresponding to HSP26, which encodes a small heat shock protein (sHsp) in yeast was up-regulated in response to CFTR expression, we examined the impact of sHsps on ERAD. First, we observed that CFTR was completely stabilized in cells lacking two partially redundant sHsps, Hsp26p and Hsp42p. Interestingly, the ERAD of a soluble and a related integral membrane protein were unaffected in yeast deleted for the genes encoding these sHsps, and CFTR polyubiquitination was also unaltered, suggesting that Hsp26p/Hsp42p are not essential for polyubiquitination. Next, we discovered that {Delta}F508-CFTR degradation was enhanced when a mammalian sHsp, {alpha}A-crystallin, was overexpressed in HEK293 cells, but wild type CFTR biogenesis was unchanged. Because {alpha}A-crystallin interacted preferentially with {Delta}F508-CFTR and because purified {alpha}A-crystallin suppressed the aggregation of CFTR’s first nucleotide-binding domain, we suggest that sHsps maintain the solubility of {Delta}F508-CFTR during the ERAD of this polypeptide.

Address correspondence to: Jeffrey L. Brodsky (jbrodsky{at}pitt.edu)






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