QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Vol. 18, Issue 3, 806-814, March 2007

This Article Full Text Full Text (PDF) Supplemental Material All Versions of this Article: E06-05-0458v1 18/3/806    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ahner, A. Articles by Brodsky, J. L. Search for Related Content PubMed PubMed Citation Articles by Ahner, A. Articles by Brodsky, J. L.

Small Heat-Shock Proteins Select F508-CFTR for Endoplasmic Reticulum-associated Degradation

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

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

Submitted May 25, 2006; Revised October 25, 2006; Accepted December 5, 2006
Monitoring Editor: Jonathan Weissman

Secreted proteins that fail to achieve their native conformations, such as cystic fibrosis transmembrane conductance regulator (CFTR) and particularly the F508-CFTR variant can be selected for endoplasmic reticulum (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 F508-CFTR degradation was enhanced when a mammalian sHsp, A-crystallin, was overexpressed in human embryonic kidney 293 cells, but wild-type CFTR biogenesis was unchanged. Because A-crystallin interacted preferentially with F508-CFTR and because purified A-crystallin suppressed the aggregation of the first nucleotide-binding domain of CFTR, we suggest that sHsps maintain the solubility of F508-CFTR during the ERAD of this polypeptide.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

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

This article has been cited by other articles:

				M. B. Metzger, M. J. Maurer, B. M. Dancy, and S. Michaelis Degradation of a Cytosolic Protein Requires Endoplasmic Reticulum-associated Degradation Machinery J. Biol. Chem., November 21, 2008; 283(47): 32302 - 32316. [Abstract] [Full Text] [PDF]