From synthesis to degradation, membrane proteins navigate interwoven networks that control their localization and activity within the cell. The PDZ (PSD-95, DIg, and ZO-1) proteins constitute a major family of trafficking regulators. Characterized by the presence of eponymous protein-protein interaction domains (PPIDs), PDZ proteins generally bind the C termini of their partners and help direct their movements throughout the cell. The targets of PDZ regulation include the cystic fibrosis transmembrane conductance regulator (CFTR), the chloride channel mutated in patients with cystic fibrosis. To identify "stabilizers", a new class of reagents that extend the half-life of AF508-CFTR, we targeted a key regulator of its post-endocytic trafficking. The CFTR-associated ligand (CAL) neg. regulates AF508-CFTR cell- surface abundance through its PDZ domain. However, CFTR interacts not only with CAL, but also with the Na/H exchanger regulatory factors NHERF1 and NHERF2, which counteract CAL's effect, enhancing the activity and the abundance of AF508-CFTR at the apical membrane. Recently described protein iCAL36 targets the CAL, but not the NHERF, PDZ domains, despite their overlapping specificities. Here, we report its biochem. characterization and functional effects in CF-patient-derived bronchial epithelial cells expressing iF5O8-CFTR (CFBE-AF cells).