Endocytic trafficking of CFTR in health and disease

Abstract

The cystic fibrosis transmembrane conductance regulator (CFTR) is a Cl-selective anion channel expressed in epithelial tissues. Mutations in CFTR lead to the genetic disease cystic fibrosis (CF). Within each epithelial cell, CFTR interacts with a large number of transient macromolecular complexes, many of which are involved in the trafficking and targeting of CFTR. Understanding how these complexes regulate the trafficking and fate of CFTR, provides a singular insight not only into the patho-physiology of cystic fibrosis, but also provides potential drug targets to help cure this debilitating disease.

FIGURE 1

Model showing main trafficking pathways taken by wild-type and ΔF508-CFTR (i) CFTR is translated in the endoplasmic reticulum (ER) where core sugars are added to the protein. Most ΔF508-CFTR is recognized as misfolded by the ER quality control and targeted for proteosomal degradation (v). Wild-type CFTR traffics to the Trans Golgi network where the cores sugars are modified into complex carbohydrates, and then trafficked to the apical plasma membrane (i). (ii) CFTR is efficiently removed from the cell surface by clathrin mediated endocytosis using trafficking signals embedded in the amino acid sequence of CFTR. (iii) From endosomes, CFTR can recycle back to the cell surface in a direct manner, or via recycling endosomes. (iv) Internalized CFTR can be directed to lysosomes for degradation.

FIGURE 2

Model showing involvement of various proteins in CFTR endocytosis and recycling CFTR (brown rectangle) is endocytosed from the apical plasma membrane in a clathrin-dependent process that requires dynamin (for vesicle fission), the μ subunit of the AP-2 adaptor complex that mediates interaction between the YDSI endocytic motif on CFTR and the clathrin lattice. The endocytosis of CFTR also requires myosin-VI, a molecular motor that drives cargo to the minus end of F-actin (i.e., inwardly directed). Several members of the RabGTPase family have been shown to modulate CFTR trafficking. Rab5 promotes endocytosis of CFTR. Exit of CFTR from early endosomes can be mediated by Rab4 which directly targets CFTR back to the plasma membrane, or by Rab7 which increases CFTR degradation by enhancing the trafficking of CFTR to late endosomes and lysosomes. Rab9 mediates CFTR trafficking from late endosomes to the trans Golgi network (TGN). Rab11 mediates CFTR trafficking from recycling endosomes to either the plasma membrane or to the TGN. RME-1 facilitates exit of CFTR from the recycling endosome. PDZ binding proteins can inhibit CFTR endocytosis from the plasma membrane, as well as facilitate recycling of internalized CFTR from early endosomes.