Journal Article

The Hsc70 co-chaperone CHIP targets immature CFTR for proteasomal degradation

Meacham, Geoffrey C., Cyr, Douglas M., Patterson, Cam, Younger, J. Michael, Zhang, Wenyue

2001

Overview

The folding of both wild-type and mutant forms of the cystic-fibrosis transmembrane-conductance regulator (CFTR), a plasma-membrane chloride-ion channel, is inefficient 1 , 2 , 3 , 4 . Most nascent CFTR is retained in the endoplasmic reticulum and degraded by the ubiquitin proteasome pathway 5 , 6 , 7 . Aberrant folding and defective trafficking of CFTRΔF508 is the principal cause of cystic fibrosis 3 , 8 , 9 , but how the endoplasmic-reticulum quality-control system targets CFTR for degradation remains unknown. CHIP is a cytosolic U-box protein that interacts with Hsc70 through a set of tetratricorepeat motifs 10 . The U-box represents a modified form of the ring-finger motif that is found in ubiquitin ligases 11 and that defines the E4 family of polyubiquitination factors 12 , 13 . Here we show that CHIP functions with Hsc70 to sense the folded state of CFTR and targets aberrant forms for proteasomal degradation by promoting their ubiquitination. The U-box appeared essential for this process because overexpresion of CHIPΔU-box inhibited the action of endogenous CHIP and blocked CFTR ubiquitination and degradation. CHIP is a co-chaperone that converts Hsc70 from a protein-folding machine into a degradation factor that functions in endoplasmic-reticulum quality control.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Animals / Biomedical and Life Sciences / Biosynthesis / brief-communication / Cancer Research / Carrier Proteins - genetics / Carrier Proteins - metabolism / Cell Biology / Cells, Cultured - cytology / Cells, Cultured - drug effects / Cells, Cultured - metabolism / Chloride channels / Control systems / Cysteine Endopeptidases - metabolism / Cystic Fibrosis Transmembrane Conductance Regulator - metabolism / Degradation / Developmental Biology / Endoplasmic reticulum / Endoplasmic Reticulum - genetics / Endoplasmic Reticulum - metabolism / Endoplasmic Reticulum - ultrastructure / Gene Deletion / HSP70 Heat-Shock Proteins - metabolism / Life Sciences / Ligases / Localization / Molecular chaperones / Molecular Chaperones - metabolism / Multienzyme Complexes - antagonists & inhibitors / Multienzyme Complexes - metabolism / Physiological aspects / Proteasome Endopeptidase Complex / Protein Folding / Protein Structure, Tertiary - physiology / Proteins / Quality control / Stem Cells / Ubiquitin-proteasome system / Ubiquitin-Protein Ligases / Ubiquitins - metabolism