Small Heat-Shock Proteins Select ΔF508-CFTR for Endoplasmic Reticulum-associated Degradation

Author:

Ahner Annette12,Nakatsukasa Kunio1,Zhang Hui2,Frizzell Raymond A.2,Brodsky Jeffrey L.1

Affiliation:

1. *Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260; and

2. Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, PA 15261

Abstract

Secreted proteins that fail to achieve their native conformations, such as cystic fibrosis transmembrane conductance regulator (CFTR) and particularly the ΔF508-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 ΔF508-CFTR degradation was enhanced when a mammalian sHsp, αA-crystallin, was overexpressed in human embryonic kidney 293 cells, but wild-type CFTR biogenesis was unchanged. Because αA-crystallin interacted preferentially with ΔF508-CFTR and because purified αA-crystallin suppressed the aggregation of the first nucleotide-binding domain of CFTR, we suggest that sHsps maintain the solubility of ΔF508-CFTR during the ERAD of this polypeptide.

Publisher

American Society for Cell Biology (ASCB)

Subject

Cell Biology,Molecular Biology

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