Delta508-CFTR traffic/ Sorting endosome formation in
The cystic fibrosis transmembrane conductance regulator
(CFTR) is a member of the ATP-binding cassette transporter
superfamily. It acts in 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 , .
The most common CFTR mutation is the loss of a Phe
residue at position 508 (deltaF508-CFTR). The mutant protein
is recognized as misfolded by the endoplasmic reticulum (ER) quality control machinery
and targeted for proteosomal degradation. This leads to inadequate amounts of poorly
functioning CFTR reaching the cell membrane to achieve Cl(-)
transport . However, growth of
deltaF508-CFTR expressing cells at reduced temperature
allows the mutant CFTR molecules to exit the ER and reach the cell surface .
CFTR internalization from plasma membrane is a very
important step in CFTR regulation.
deltaF508-CFTR and wtCFTR may be internalizated from plasma membrane in
similar clathrin-dependent manner. Then coated-pit-derived primary endocytic vesicles are
fused with sorting endosomes. The fusion event is regulated by a member of RAS oncogene
family Rab-5A, Early endosome antigen 1
(EEA1) ,  and Soluble
N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) , .
At this phase, quality control at early endosome may eliminate
deltaF508-CFTR as well. Components of the Ub-dependent
endosomal sorting machinery Hepatocyte growth factor-regulated tyrosine kinase substrate
(Hrs), Signal transducing adaptor molecule 2
(STAM2), Tumor susceptibility gene 101
(TSG101), Vacuolar protein sorting 25 homolog
(Vps25) and Chromatin modifying protein 4B
(CHMP4B) are selectively bound to
deltaF508-CFTR and stimulate lysosomal degradation of the
misfolded CFTR .
The maturation of sorting endosomes to late endosomes is realized with participation
of a member of the RAS oncogene family Rab7 via unknown
mechanism , , .
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