Selective inhibition of endoplasmic reticulum-associated degradation rescues ΔF508-cystic fibrosis transmembrane regulator and suppresses interleukin-8 levels: Therapeutic implications

Neeraj Vij, Shengyun Fang, Pamela L. Zeitlin

Research output: Contribution to journalArticlepeer-review

Abstract

Endoplasmic reticulum (ER)-associated degradation (ERAD) is the major quality control pathway of the cell. The most common diseasecausing protein folding mutation, ΔF508-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 NFκB-mediated IL8 activation. The inhibition of the majorstress-inducible transcription factor CHOP (CCAAT/enhancer-binding protein homologous protein)/GADD153 together with bortezomib was most effective in repressing NFκB-mediated IL8 activation compared with interference of VCP,MLN-273(proteasome inhibitor), or 4-phenylbutyrate (histone deacetylase inhibitor). Immunoprecipitation of ΔF508-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.

Original languageEnglish (US)
Pages (from-to)17369-17378
Number of pages10
JournalJournal of Biological Chemistry
Volume281
Issue number25
DOIs
StatePublished - Jun 23 2006

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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