Rab-9, CFTR, Syntaxin 8, VTI1B, Rab-7, RILP, Rab-27A, VAMP8, MUNC13-4, 1,2-diacyl-glycerol 3-phosphoinositol, CFTR, ATP + 1,2-diacyl-glycerol 3-phosphoinositol = ADP + 1-(1,2-diacyl-glycerol 3-phospho)-inositol 3-phosphate, PI3K reg class III, PI3K cat class III, Slp5, 1-(1,2-diacyl-glycerol 3-phospho)-inositol 3-phosphate
wtCFTR and deltaF508 traffic/ Late endosome and Lysosome
(norm and CF)
The cystic fibrosis transmembrane conductance regulator ( CFTR ) is a member of the ATP-binding cassette transporter superfamily. It acts in the apical part of the epithelial cells as a plasma-membrane cyclic AMP-activated chloride anion, bicarbonate anion and glutathione channel , , . Cell surface expression of the CFTR is a highly regulated intracellular process , .
CFTR internalization from plasma membrane is a very important step in CFTR regulation. CFTR may be internalizated from plasma membrane in a clathrin-dependent manner. Then coated-pit-derived primary endocytic vesicles are fused with sorting endosomes. The maturation of sorting endosomes to late endosomes is realized with participation of a member of the RAS oncogene family Rab7 via an unknown mechanism , , .
Late endosomes may fuse with other late endosomes or the lysosome via SNARE-mediated mechanism , , . In addition, Rab7 is directly involved in the aggregation and fusion of late endocytic structures/lysosomes , .
Rab GTPase Rab-27A, which plays a pivotal role in secretions and lysosomal degradation, negatively regulates CFTR channel activity by physically interacting with it and impairing it from reaching the plasma membrane, thus increasing an internal or cytosolic CFTR pool, whereas S ynaptotagmin-like 5 ( Slp5 ) impairs CFTR ability to interact with Rab-27A and may rescue it via competition with Rab-27A .
The most common CFTR mutation is the loss of a Phe residue at position 508 ( deltaF508 -CFTR ). deltaF508-CFTR membrane expression is reduced compare with wtCFTR and its lysosomal degradation is realized in the same way as wt CFTR, although more intensively .