This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The CFTR inhibitory factor Cif is a Pseudomonas aeruginosa virulence factor that suppresses apical-membrane abundance of CFTR and class I MHC proteins in airway epithelial cells. As a result, it can sabotage both the innate and acquired immune responses in the lung. Cif expression is detected in clinical isolates from patients with cystic fibrosis and appears to be up-regulated in non-muciod, compared to mucoid strains. Although Cif is a potential therapeutic target, the pathway of Cif-mediated breakdown of CFTR is unclear. Following endocytosis, interaction of CFTR with the CFTR associated ligand CAL can facilitate lysosomal degradation. Our hypothesis is that Cif triggers endocytosis of CFTR, causing it to enter a CAL-mediated degradative pathway. To test this hypothesis, we plan to study the functional and molecular interactions of CAL and Cif in airway epithelial cells.
Our aims are (1) to test the hypothesis that CAL knockdown can block the action of Cif and (2) to test the hypothesis that Cif treatment can enhance the intracellular association of CAL and CFTR.
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