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

Abstract

The folding of both wild-type and mutant forms of the cystic-fibrosis transmembrane-conductance regulator (CFTR), a plasma-membrane chloride-ion channel, is inefficient1,2,3,4. Most nascent CFTR is retained in the endoplasmic reticulum and degraded by the ubiquitin proteasome pathway5,6,7. Aberrant folding and defective trafficking of CFTRΔF508 is the principal cause of cystic fibrosis3,8,9, 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 motifs10. The U-box represents a modified form of the ring-finger motif that is found in ubiquitin ligases11 and that defines the E4 family of polyubiquitination factors12,13. 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.

Cite this article

Meacham, G., Patterson, C., Zhang, W. et al. The Hsc70 co-chaperone CHIP targets immature CFTR for proteasomal degradation. Nat Cell Biol 3, 100–105 (2001). https://doi.org/10.1038/35050509

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