Delta508-CFTR traffic / Sorting endosome formation in CF

print

Select Species:

Click on a target from the pathway image to view related information. Zoom     View Legend

photo_map
 


Delta508-CFTR traffic/ Sorting endosome formation in CF.

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 [1], [2], [3]. Cell surface expression of the CFTR is a highly regulated intracellular process [4], [5].

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 [6]. However, growth of deltaF508-CFTR expressing cells at reduced temperature allows the mutant CFTR molecules to exit the ER and reach the cell surface [5].

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) [7], [8] and Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) [9], [10].

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 [11].

The maturation of sorting endosomes to late endosomes is realized with participation of a member of the RAS oncogene family Rab7 via unknown mechanism [8], [12], [13].

References:

  1. Kogan I, Ramjeesingh M, Li C, Kidd JF, Wang Y, Leslie EM, Cole SP, Bear CE
    CFTR directly mediates nucleotide-regulated glutathione flux. The EMBO journal 2003 May 1;22(9):1981-9
  2. Chan HC, Shi QX, Zhou CX, Wang XF, Xu WM, Chen WY, Chen AJ, Ni Y, Yuan YY
    Critical role of CFTR in uterine bicarbonate secretion and the fertilizing capacity of sperm. Molecular and cellular endocrinology 2006 May 16;250(1-2):106-13
  3. Gadsby DC, Vergani P, Csanady L
    The ABC protein turned chloride channel whose failure causes cystic fibrosis. Nature 2006 Mar 23;440(7083):477-83
  4. Guggino WB, Stanton BA
    New insights into cystic fibrosis: molecular switches that regulate CFTR. Nature reviews. Molecular cell biology 2006 Jun;7(6):426-36
  5. Ameen N, Silvis M, Bradbury NA
    Endocytic trafficking of CFTR in health and disease. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society 2007 Jan;6(1):1-14
  6. Dubin PJ, McAllister F, Kolls JK
    Is cystic fibrosis a TH17 disease? Inflammation research : official journal of the European Histamine Research Society ... [et al.] 2007 Jun;56(6):221-7
  7. Woodman PG
    Biogenesis of the sorting endosome: the role of Rab5. Traffic (Copenhagen, Denmark) 2000 Sep;1(9):695-701
  8. Gentzsch M, Chang XB, Cui L, Wu Y, Ozols VV, Choudhury A, Pagano RE, Riordan JR
    Endocytic trafficking routes of wild type and DeltaF508 cystic fibrosis transmembrane conductance regulator. Molecular biology of the cell 2004 Jun;15(6):2684-96
  9. Maxfield FR, McGraw TE
    Endocytic recycling. Nature reviews. Molecular cell biology 2004 Feb;5(2):121-32
  10. Hong W
    SNAREs and traffic. Biochimica et biophysica acta 2005 Jun 30;1744(2):120-44
  11. Sharma M, Pampinella F, Nemes C, Benharouga M, So J, Du K, Bache KG, Papsin B, Zerangue N, Stenmark H, Lukacs GL
    Misfolding diverts CFTR from recycling to degradation: quality control at early endosomes. The Journal of cell biology 2004 Mar 15;164(6):923-33
  12. Feng Y, Press B, Wandinger-Ness A
    Rab 7: an important regulator of late endocytic membrane traffic. The Journal of cell biology 1995 Dec;131(6 Pt 1):1435-52
  13. Somsel Rodman J, Wandinger-Ness A
    Rab GTPases coordinate endocytosis. Journal of cell science 2000 Jan;113 Pt 2:183-92

  1. Kogan I, Ramjeesingh M, Li C, Kidd JF, Wang Y, Leslie EM, Cole SP, Bear CE
    CFTR directly mediates nucleotide-regulated glutathione flux. The EMBO journal 2003 May 1;22(9):1981-9
  2. Chan HC, Shi QX, Zhou CX, Wang XF, Xu WM, Chen WY, Chen AJ, Ni Y, Yuan YY
    Critical role of CFTR in uterine bicarbonate secretion and the fertilizing capacity of sperm. Molecular and cellular endocrinology 2006 May 16;250(1-2):106-13
  3. Gadsby DC, Vergani P, Csanady L
    The ABC protein turned chloride channel whose failure causes cystic fibrosis. Nature 2006 Mar 23;440(7083):477-83
  4. Guggino WB, Stanton BA
    New insights into cystic fibrosis: molecular switches that regulate CFTR. Nature reviews. Molecular cell biology 2006 Jun;7(6):426-36
  5. Ameen N, Silvis M, Bradbury NA
    Endocytic trafficking of CFTR in health and disease. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society 2007 Jan;6(1):1-14
  6. Dubin PJ, McAllister F, Kolls JK
    Is cystic fibrosis a TH17 disease? Inflammation research : official journal of the European Histamine Research Society ... [et al.] 2007 Jun;56(6):221-7
  7. Woodman PG
    Biogenesis of the sorting endosome: the role of Rab5. Traffic (Copenhagen, Denmark) 2000 Sep;1(9):695-701
  8. Gentzsch M, Chang XB, Cui L, Wu Y, Ozols VV, Choudhury A, Pagano RE, Riordan JR
    Endocytic trafficking routes of wild type and DeltaF508 cystic fibrosis transmembrane conductance regulator. Molecular biology of the cell 2004 Jun;15(6):2684-96
  9. Maxfield FR, McGraw TE
    Endocytic recycling. Nature reviews. Molecular cell biology 2004 Feb;5(2):121-32
  10. Hong W
    SNAREs and traffic. Biochimica et biophysica acta 2005 Jun 30;1744(2):120-44
  11. Sharma M, Pampinella F, Nemes C, Benharouga M, So J, Du K, Bache KG, Papsin B, Zerangue N, Stenmark H, Lukacs GL
    Misfolding diverts CFTR from recycling to degradation: quality control at early endosomes. The Journal of cell biology 2004 Mar 15;164(6):923-33
  12. Feng Y, Press B, Wandinger-Ness A
    Rab 7: an important regulator of late endocytic membrane traffic. The Journal of cell biology 1995 Dec;131(6 Pt 1):1435-52
  13. Somsel Rodman J, Wandinger-Ness A
    Rab GTPases coordinate endocytosis. Journal of cell science 2000 Jan;113 Pt 2:183-92

Target Details

Click on a target from the pathway image to view related information.