Valosin Containing Protein (VCP)/p97 Gene Inhibition Rescues cystic Fibrosis Transmembrane Regulator (CFTR) from Endoplasmic Reticulum Mediated Degradation

Endoplasmic reticulum (ER)-associated protein degradation (ERAD) eliminates misfolded, damaged, or mutant proteins with abnormal conformation from the cell. The most common disease-causing protein folding mutation is deletion of phenylalanine at position 508 of the cystic fibrosis transmembrane regulator (delta F508-CFTR). This mutation results in a temperature-sensitive folding defect and premature degradation by ERAD, which ultimately leads to cystic fibrosis. The p97/valosin-containing protein (VCP) physically interacts with gp78/autocrine motility factor receptor to couple ubiquitination, retrotranslocation, and proteasome degradation of misfolded proteins. Furthermore, p97/VCP and gp78 form complexes with CFTR during translocation from the ER for degradation by the cytosolic proteasome. JHU researchers have demonstrated that interference of the VCP-CFTR complex promoted accumulation of immature CFTR in the ER and partial rescue of functional chloride channels to the cell surface. In addition, disruption of the VCP-CFTR complex suppressed levels of (IL)-8, the major inflammatory cytokine in cystic fibrosis. Description (Set) Proposed Use (Set) Inhibiting the degradation delta F508-CFTR through disruption of the VCP-CFTR complex may provide a new method of treating patients with cystic fibrosis. This technology may also allow the development of cystic fibrosis drugs that target the ubiquitin-proteasome pathway and provide insights into their efficacy.

Inventor(s): Zeitlin, Pam

Type of Offer: Licensing



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