Delta508-CFTR traffic / ER-to-Golgi in CF

Delta508-CFTR traffic/ ER-to-Golgi 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). It 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].

Export of CFTR from ER to the Golgi may be realized in Coat protein complex-II (COPII)-dependent manner [7], [8]. It is supposed that binding of COPII to deltaF508-CFTR is disrupted, thus preventing membrane expression of deltaF508-CFTR [9].

A Golgi associated PDZ and coiled-coil motif containing (PIST) regulates CFTR trafficking. PIST causes a reduction in the number of CFTR channels in the plasma membrane and facilitates trafficking of CFTR to lysosomes [10], [11], [12]. PIST action is activated by Syntaxin 6 [13], (Cheng et al., The 21st annual north American cystic fibrosis conference, California, 2007) and is inhibited by Ras homolog gene family, member Q (TC10) [14].

CFTR modified in ER and/or Golgi may be delivered from the Golgi to the apical membrane, possibly, with participation of coat protein complex Coatomer [15].

References:

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   CFTR directly mediates nucleotide-regulated glutathione flux. The EMBO journal 2003 May 1;22(9):1981-9
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   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
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   Is cystic fibrosis a TH17 disease? Inflammation research : official journal of the European Histamine Research Society ... [et al.] 2007 Jun;56(6):221-7
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   Non-conventional trafficking of the cystic fibrosis transmembrane conductance regulator through the early secretory pathway. The Journal of biological chemistry 2002 Mar 29;277(13):11401-9
8. Gurkan C, Stagg SM, Lapointe P, Balch WE
   The COPII cage: unifying principles of vesicle coat assembly. Nature reviews. Molecular cell biology 2006 Oct;7(10):727-38
9. Wang X, Matteson J, An Y, Moyer B, Yoo JS, Bannykh S, Wilson IA, Riordan JR, Balch WE
   COPII-dependent export of cystic fibrosis transmembrane conductance regulator from the ER uses a di-acidic exit code. The Journal of cell biology 2004 Oct 11;167(1):65-74
10. Cheng J, Moyer BD, Milewski M, Loffing J, Ikeda M, Mickle JE, Cutting GR, Li M, Stanton BA, Guggino WB
    A Golgi-associated PDZ domain protein modulates cystic fibrosis transmembrane regulator plasma membrane expression. The Journal of biological chemistry 2002 Feb 1;277(5):3520-9
11. Cheng J, Wang H, Guggino WB
    Modulation of mature cystic fibrosis transmembrane regulator protein by the PDZ domain protein CAL. The Journal of biological chemistry 2004 Jan 16;279(3):1892-8
12. Guggino WB
    The cystic fibrosis transmembrane regulator forms macromolecular complexes with PDZ domain scaffold proteins. Proceedings of the American Thoracic Society 2004;1(1):28-32
13. Charest A, Lane K, McMahon K, Housman DE
    Association of a novel PDZ domain-containing peripheral Golgi protein with the Q-SNARE (Q-soluble N-ethylmaleimide-sensitive fusion protein (NSF) attachment protein receptor) protein syntaxin 6. The Journal of biological chemistry 2001 Aug 3;276(31):29456-65
14. Cheng J, Wang H, Guggino WB
    Regulation of cystic fibrosis transmembrane regulator trafficking and protein expression by a Rho family small GTPase TC10. The Journal of biological chemistry 2005 Feb 4;280(5):3731-9
15. Godi A, Di Campli A, Konstantakopoulos A, Di Tullio G, Alessi DR, Kular GS, Daniele T, Marra P, Lucocq JM, De Matteis MA
    FAPPs control Golgi-to-cell-surface membrane traffic by binding to ARF and PtdIns(4)P. Nature cell biology 2004 May;6(5):393-404