CFTR is a chloride ion channel mainly expressed in epithelial tissues, and its mutation causes Cystic fibrosis (CF). Previous reports have shown that infection-independent inflammatory cytokine release in the airway epithelium occurs in the early stages of CF pathology. However, the molecular mechanism of this CFTR-loss-dependent sterile inflammation has not yet been clarified. We focused on the CFTR interactome changes associated with CFTR mutations and searched for molecules that interact only with the mature form of CFTR by the BioID method. As a result, CFTR interacts with receptor-type tyrosine kinase EPHX.
Interestingly, CFTR-loss-dependent IL-8 production was significantly suppressed by EPHX knockdown and EPHX signal inhibitors. Since EPHX was shown to activate a ligand-independent pathway in the absence of CFTR, we investigated whether CFTR affects EPHX and its ligand binding. As a result, EPHX and the ligand interaction were reduced in the absence of CFTR. From these results, CFTR maintains ligand binding to EPHX under normal conditions, but during the loss of CFTR function, EPHX and ligand binding decreases, and the ligand-independent pathway of EPHX is activated. Targeting EPHX may lead to the development of treatments for sterile inflammation in the early stage of CF.