CFTR channel opening requires phosphorylation by cAMP-dependent protein kinases and hydrolyzable MgATP. Indeed, CFTR regulation is complex and involves dimerization of the protein and interdomain interactions. Syntaxin 1A, EBP50, E3KARP, the m subunit of the endocytic clathrin adaptor complex, cysteine string proteins and annexin A5 are CFTRbinding proteins, but the extent to which CFTR channels are regulated by protein-protein interactions remains largely unknown. To date, over 1910 mutations have been identified in the CFTR gene and a classification of mutations by which different mechanisms induce CF has been proposed. Among these mutations, the CF-causing missense mutation G551D-CFTR exhibits normal expression at the cell surface but it is associated with severe disease. Indeed, it lacks channel activation mediated by ATP. G551D-CFTR is not a common mutation in the CF patients but the clinical phenotype is considered very severe. Therefore, efforts have been taken to overcome the G551D-CFTR defect. Biochemical studies on purified and reconstituted G551D-CFTR showed the potentiation of the ATPase activity by VRT-532. Nevertheless, VRT-532 did not affect the ATPase activity of the Wt CFTR. This supported the idea that this compound corrects the specific molecular defect of this mutant by a direct or indirect binding, stabilizing an intramolecular interaction. This potentiator seems to have a mutant specificity which may be due to CFTR interacting proteins. As it is suggested that G551D-CFTR has different binding partners when compared to Wt-CFTR, the aim of the present study was to identify specific interacting proteins of G551DCFTR. The proteins linked to G551D-CFTR were resolved by 2D-gel electrophoresis. Among the detected spots, one spot exhibited a high intensity and was subjected to Mass Spectrometry. MS revealed that the corresponding protein was calumenin. We found that its basal expression was not modified in G551DCFTR expressing cells when compared to Wt-CFTR expressing cells. Using co-immunoprecipitation, we found that FG-4592 molecular weight calumenin was bound to the G551D-CFTR protein. The co-immunoprecipitation experiment also indicated that calumenin was also bound to WtCFTR. Nevertheless, the amount of bound calumenin was higher in the G551D-CFTR complex than in the Wt-CFTR one. The calumenin – CFTR interaction was further confirmed by computational interaction prediction and by Surface Plasmon Resonance. In order to know whether calumenin was localized in the Endoplasmic Reticulum in our cell model and whether the interaction takes place in the ER in which calumenin is known to be present, immunofluorescence was performed. We found that the calumenin – CFTR interaction is indeed only present in the ER of the cells. Because calumenin expression is modulated in cells expressing the most frequent CFTR mutant together with Grp78/Bip which is a hallmark of the Unfolded Protein Response and because we found an increased level of calumenin linked to G551D-CFTR, we assessed the Grp78 expression in the cells.