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Published 20 December 2004. doi:10.1083/jcb.200410065
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 167, Number 6, 1075-1085
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Article

 A foldable CFTR{Delta}F508 biogenic intermediate accumulates upon inhibition of the Hsc70–CHIP E3 ubiquitin ligase

J. Michael Younger1,2, Hong-Yu Ren1,2, Liling Chen1,2, Chun-Yang Fan1,2, Andrea Fields1,2, Cam Patterson1, and Douglas M. Cyr1,2

1 Department of Cell and Developmental Biology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599
2 The Cystic Fibrosis Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599

Correspondence to D.M. Cyr: dmcyr{at}med.unc.edu

CFTR{Delta}F508 exhibits a correctable protein-folding defect that leads to its misfolding and premature degradation, which is the cause of cystic fibrosis (CF). Herein we report on the characterization of the CFTR{Delta}F508 biogenic intermediate that is selected for proteasomal degradation and identification of cellular components that polyubiquitinate CFTR{Delta}F508. Nonubiquitinated CFTR{Delta}F508 accumulates in a kinetically trapped, but folding competent conformation, that is maintained in a soluble state by cytosolic Hsc70. Ubiquitination of Hsc70-bound CFTR{Delta}F508 requires CHIP, a U box containing cytosolic cochaperone. CHIP is demonstrated to function as a scaffold that nucleates the formation of a multisubunit E3 ubiquitin ligase whose reconstituted activity toward CFTR is dependent upon Hdj2, Hsc70, and the E2 UbcH5a. Inactivation of the Hsc70–CHIP E3 leads CFTR{Delta}F508 to accumulate in a nonaggregated state, which upon lowering of cell growth temperatures, can fold and reach the cell surface. Inhibition of CFTR{Delta}F508 ubiquitination can increase its cell surface expression and may provide an approach to treat CF.

Abbreviations used in this paper: ApoB48, apolipoprotein B48; BFA, brefeldin A; CF, cystic fibrosis; ERQC, endoplasmic reticulum quality control system; NBD, nucleotide binding domain; TCR{alpha}, T cell receptor {alpha} subunit; TPR, tetratricopeptide repeat motifs.


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