wtCFTR and deltaF508 traffic / Late endosome and Lysosome (norm and CF)

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

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 [6], [7], [8].

Late endosomes may fuse with other late endosomes or the lysosome via SNARE-mediated mechanism [9], [10], [11]. In addition, Rab7 is directly involved in the aggregation and fusion of late endocytic structures/lysosomes [12], [13].

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 Synaptotagmin-like 5 (Slp5) impairs CFTR ability to interact with Rab-27A and may rescue it via competition with Rab-27A [14].

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 wtCFTR, although more intensively [15].

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. 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
7. Somsel Rodman J, Wandinger-Ness A
   Rab GTPases coordinate endocytosis. Journal of cell science 2000 Jan;113 Pt 2:183-92
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. Bilan F, Thoreau V, Nacfer M, Derand R, Norez C, Cantereau A, Garcia M, Becq F, Kitzis A
   Syntaxin 8 impairs trafficking of cystic fibrosis transmembrane conductance regulator (CFTR) and inhibits its channel activity. Journal of cell science 2004 Apr 15;117(Pt 10):1923-35
10. Pryor PR, Mullock BM, Bright NA, Lindsay MR, Gray SR, Richardson SC, Stewart A, James DE, Piper RC, Luzio JP
    Combinatorial SNARE complexes with VAMP7 or VAMP8 define different late endocytic fusion events. EMBO reports 2004 Jun;5(6):590-5
11. Hong W
    SNAREs and traffic. Biochimica et biophysica acta 2005 Jun 30;1744(2):120-44
12. Bucci C, Thomsen P, Nicoziani P, McCarthy J, van Deurs B
    Rab7: a key to lysosome biogenesis. Molecular biology of the cell 2000 Feb;11(2):467-80
13. Stein MP, Feng Y, Cooper KL, Welford AM, Wandinger-Ness A
    Human VPS34 and p150 are Rab7 interacting partners. Traffic (Copenhagen, Denmark) 2003 Nov;4(11):754-71
14. Saxena SK, Kaur S
    Rab27a negatively regulates CFTR chloride channel function in colonic epithelia: involvement of the effector proteins in the regulatory mechanism. Biochemical and biophysical research communications 2006 Jul 21;346(1):259-67
15. 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