Figure 2
EHF-dependent gene regulation in relation to p.Phe508del-CFTR biosynthesis, trafficking and post-translational modification. Mature, fully glycosylated and functional p.Phe508del-CFTR—emphasized as a green line at the apical membrane (AM) – reaches the apical membrane through trafficking pathways36, 37 illustrated as green arrows (a). These encompass biosynthesis and insertion into the lipid bilayer (IA), utilization of the ER-associated folding pathway (ERAF)37, passage through the ER, ERGIC (IB) and Golgi-compartments, post-translational modifications (PTMs) and finally, transport of mature p.Phe508del-CFTR to subapically localized vesicles (IC) and to the AM (ID). The alternative CFTR maturation pathway that bypasses the ERGIC and Golgi compartments49 is shown (II). In contrast, pathways that lead to degradation of p.Phe508del-CFTR36, 37 are depicted in orange. These encompass the ER-associated degradation pathway ER-associated degradation (ERAD)37 that leads to degradation in the proteasome (PR) and the retrograde traffic of endosomes from the subapical compartment (III) toward the lysosome (LY). EHF-dependent differentially regulated genes whose products have been annotated to partake in any of these pathways crucial to p.Phe508del-CFTR biosynthesis, maturation and trafficking are shown in b–j. Gene products for which the subcellular localization cannot be specified are listed in j. Forty trafficking and maturation genes whose expression are upregulated among the nine p.Phe508del-CFTR homozygous carriers of at least one frequent EHF allele are shown in orange. Fifty-eight trafficking and maturation genes whose expression are upregulated among the seven p.Phe508del-CFTR homozygous carriers of two rare EHF alleles are shown in green.
