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J. Biol. Chem., Vol. 281, Issue 25, 17369-17378, June 23, 2006
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F508-Cystic Fibrosis Transmembrane Regulator and Suppresses Interleukin-8 Levels
1
From the
Division of Pediatric Respiratory Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland 21287 and the Medical Biotechnology Center, University of Maryland Biotechnology Institute, Baltimore, Maryland 21201
Endoplasmic reticulum (ER)-associated degradation (ERAD) is the major quality control pathway of the cell. The most common disease-causing protein folding mutation, 
F508-cystic fibrosis transmembrane regulator (CFTR), is destroyed by ERAD to cause cystic fibrosis (CF). p97/valosin-containing protein (VCP) physically interacts with gp78/autocrine motility factor receptor to couple ubiquitination, retrotranslocation, and proteasome degradation of misfolded proteins. We show here that p97/VCP and gp78 form complexes with CFTR during translocation from the ER for degradation by the cytosolic proteasome. Interference in the VCP-CFTR complex promoted accumulation of immature CFTR in the ER and partial rescue of functional chloride channels to the cell surface. Moreover, under these conditions, interleukin-8 (IL8), the expression of which is regulated by the proteasome, was reduced. Inhibition of the proteasome with bortezomib (PS-341/Velcade) also rescued CFTR, but with less efficiency, and suppressed NF
B-mediated IL8 activation. The inhibition of the major stress-inducible transcription factor CHOP (CCAAT/enhancer-binding protein homologous protein)/GADD153 together with bortezomib was most effective in repressing NFB-mediated IL8 activation compared with interference of VCP, MLN-273 (proteasome inhibitor), or 4-phenylbutyrate (histone deacetylase inhibitor). Immunoprecipitation of F508-CFTR from primary CF bronchial epithelial cells confirmed the interaction with VCP and associated chaperones in CF. We conclude that VCP is an integral component of ERAD and cellular stress pathways induced by the unfolded protein response and may be central to the efficacy of CF drugs that target the ubiquitin-proteasome pathway.
Received for publication, January 18, 2006 , and in revised form, March 30, 2006.
* This work was supported by National Institutes of Health Grant RO1 HL59410. IB3-1 cells are under a licensing agreement between Pfizer Inc., Japan Tobacco Inc., and The Johns Hopkins University. Dr. Zeitlin is entitled to a fee received by the University on sales of this cell line. The terms of this arrangement are being managed by the University in accordance with its conflict of interest policies. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 To whom correspondence should be addressed: Dept. of Pediatrics, Johns Hopkins School of Medicine, 600 N. Wolfe St., Park 316, Baltimore, MD 21287. Tel.: 410-614-5637; Fax: 410-955-1030; E-mail: pzeitlin{at}jhmi.edu.
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