Endoplasmic reticulum (ER)-associated degradation (ERAD) is the major quality control pathway of the cell. The most common disease-causing protein folding mutation, DeltaF508-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 NFkappaB-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 NFkappaB-mediated
IL8 activation compared with interference of VCP,
MLN-273 (
proteasome inhibitor), or
4-phenylbutyrate (
histone deacetylase inhibitor). Immunoprecipitation of
DeltaF508-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.