wtCFTR and delta508-CFTR traffic/ Generic schema (norm and
CF)
The cystic fibrosis transmembrane conductance regulator
(CFTR) is a member of the ATP-binding cassette transporter
superfamily and 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 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]. CFTR
stabilization in plasma membrane depends on participation of different proteins. For
example, Solute carrier family 9 member 3 regulator 1
(EBP50) [16], Copper metabolism domain
containing 1 (COMMD1) (Drevillion, L et al., The 21st annual
north American cystic fibrosis conference, California, 2007), Protein kinase C epsilon
(PKC-epsilon) [17] Filamin
A and Filamin B [18] and
cAMP-dependent protein kinase (PKA) stabilize
CFTR [19]. Syntaxin
1A/ Synaptosomal-associated protein 23kDa
(SNAP-23) have negative influence on
CFTR membrane expression [19], [20].
CFTR may be internalizated from plasma membrane in
Clathrin-dependent manner. The classical key components of
Clathrin-dependent endocytosis of CFTR are Adaptor-related
protein complex 2 (AP complex 2) [21], [22] and Disabled homolog 2 mitogen-responsive phosphoprotein
(Dab2) [23]. In addition, some cargo-unspecified
adaptors may participate in this process [24], [25], [26].
Next phase is the fusion of coated-pit-derived primary endocytic vesicles with sorting
endosomes. It is regulated,for example,. by a member of RAS oncogene family
Rab-5A [27], [28] and Soluble
N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) [29], [30].
At this phase quality control at early endosome may eliminate
deltaF508-CFTR too. 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 [31].
The maturation of sorting endosomes to late endosomes is facilitated by a member of
the RAS oncogene family Rab7 via an unknown mechanism [28], [32], [33].
Late endosomes may participate in fusion with the other late endosomes or lysosome via
SNARE-mediated mechanism [30], [34], [35]. In
addition, Rab7 is directly involved in the aggregation and
fusion of late endocytic structures/lysosomes [36], [37].
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 internal or cytosolic
CFTR pool [38], [39].
Moreover, CFTR may be delivered to the cell surface via
the shot pathway from endosomes via different recycling endosomes [5], [29]. It is realized mainly via Rab-4 and/or
Rab-11A-dependent mechanisms [39].
Endogenous Rab-11A, a member of RAS oncogene family,
forms a complex with Myosin Vb which facilitates recycling
of CFTR from recycling endosomes to the apical plasma
membrane in polarized epithelial cells [40], [41], [42]. Rab-4 protein group belongs to RAS oncogene
family which controls recycling events from endosome to the plasma membrane, fusion, and
degradation inhibits CFTR chloride channel activity by
diminishing its cell surface expression [43].
It was shown that regulation of expression or activity of some member
CFTR traffic pathway may lead to the membrane expression of
deltaF508-CFTR. For example,
over-regulation of Rab-11A
[28], EBP50 [44] and down-regulation
Rab-5A, Rab-7 [28]
and Syntaxin 6 (Cheng et al., The 21st annual north American
cystic fibrosis conference, California, 2007) have this effect.
References:
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CFTR directly mediates nucleotide-regulated glutathione flux.
The EMBO journal 2003 May 1;22(9):1981-9
- 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
- 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
- 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
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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
- 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
- Yoo JS, Moyer BD, Bannykh S, Yoo HM, Riordan JR, Balch WE
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
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The COPII cage: unifying principles of vesicle coat assembly.
Nature reviews. Molecular cell biology 2006 Oct;7(10):727-38
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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
- 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
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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
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The cystic fibrosis transmembrane regulator forms macromolecular complexes with PDZ domain scaffold proteins.
Proceedings of the American Thoracic Society 2004;1(1):28-32
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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
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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
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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
- Haggie PM, Stanton BA, Verkman AS
Increased diffusional mobility of CFTR at the plasma membrane after deletion of its C-terminal PDZ binding motif.
The Journal of biological chemistry 2004 Feb 13;279(7):5494-500
- Auerbach M, Liedtke CM
Role of the scaffold protein RACK1 in apical expression of CFTR.
American journal of physiology. Cell physiology 2007 Jul;293(1):C294-304
- Thelin WR, Chen Y, Gentzsch M, Kreda SM, Sallee JL, Scarlett CO, Borchers CH, Jacobson K, Stutts MJ, Milgram SL
Direct interaction with filamins modulates the stability and plasma membrane expression of CFTR.
The Journal of clinical investigation 2007 Feb;117(2):364-74
- Chang SY, Di A, Naren AP, Palfrey HC, Kirk KL, Nelson DJ
Mechanisms of CFTR regulation by syntaxin 1A and PKA.
Journal of cell science 2002 Feb 15;115(Pt 4):783-91
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CFTR chloride channels are regulated by a SNAP-23/syntaxin 1A complex.
Proceedings of the National Academy of Sciences of the United States of America 2002 Sep 17;99(19):12477-82
- Weixel KM, Bradbury NA
The carboxyl terminus of the cystic fibrosis transmembrane conductance regulator binds to AP-2 clathrin adaptors.
The Journal of biological chemistry 2000 Feb 4;275(5):3655-60
- Weixel KM, Bradbury NA
Mu 2 binding directs the cystic fibrosis transmembrane conductance regulator to the clathrin-mediated endocytic pathway.
The Journal of biological chemistry 2001 Dec 7;276(49):46251-9
- Swiatecka-Urban A, Boyd C, Coutermarsh B, Karlson KH, Barnaby R, Aschenbrenner L, Langford GM, Hasson T, Stanton BA
Myosin VI regulates endocytosis of the cystic fibrosis transmembrane conductance regulator.
The Journal of biological chemistry 2004 Sep 3;279(36):38025-31
- Wendland B
Epsins: adaptors in endocytosis?
Nature reviews. Molecular cell biology 2002 Dec;3(12):971-7
- Szymkiewicz I, Shupliakov O, Dikic I
Cargo- and compartment-selective endocytic scaffold proteins.
The Biochemical journal 2004 Oct 1;383(Pt 1):1-11
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Life of a clathrin coat: insights from clathrin and AP structures.
Nature reviews. Molecular cell biology 2006 Jan;7(1):32-44
- Woodman PG
Biogenesis of the sorting endosome: the role of Rab5.
Traffic (Copenhagen, Denmark) 2000 Sep;1(9):695-701
- 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
- Maxfield FR, McGraw TE
Endocytic recycling.
Nature reviews. Molecular cell biology 2004 Feb;5(2):121-32
- Hong W
SNAREs and traffic.
Biochimica et biophysica acta 2005 Jun 30;1744(2):120-44
- 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
- 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
- Somsel Rodman J, Wandinger-Ness A
Rab GTPases coordinate endocytosis.
Journal of cell science 2000 Jan;113 Pt 2:183-92
- 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
- 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
- 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
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Human VPS34 and p150 are Rab7 interacting partners.
Traffic (Copenhagen, Denmark) 2003 Nov;4(11):754-71
- 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
- Saxena SK, Kaur S
Regulation of epithelial ion channels by Rab GTPases.
Biochemical and biophysical research communications 2006 Dec 22;351(3):582-7
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Rme-1 regulates the recycling of the cystic fibrosis transmembrane conductance regulator.
American journal of physiology. Cell physiology 2003 Nov;285(5):C1009-18
- Swiatecka-Urban A, Brown A, Moreau-Marquis S, Renuka J, Coutermarsh B, Barnaby R, Karlson KH, Flotte TR, Fukuda M, Langford GM, Stanton BA
The short apical membrane half-life of rescued {Delta}F508-cystic fibrosis transmembrane conductance regulator (CFTR) results from accelerated endocytosis of {Delta}F508-CFTR in polarized human airway epithelial cells.
The Journal of biological chemistry 2005 Nov 4;280(44):36762-72
- Swiatecka-Urban A, Talebian L, Kanno E, Moreau-Marquis S, Coutermarsh B, Hansen K, Karlson KH, Barnaby R, Cheney RE, Langford GM, Fukuda M, Stanton BA
Myosin Vb is required for trafficking of the cystic fibrosis transmembrane conductance regulator in Rab11a-specific apical recycling endosomes in polarized human airway epithelial cells.
The Journal of biological chemistry 2007 Aug 10;282(32):23725-36
- Saxena SK, Kaur S, George C
Rab4GTPase modulates CFTR function by impairing channel expression at plasma membrane.
Biochemical and biophysical research communications 2006 Mar 3;341(1):184-91
- Bossard F, Robay A, Toumaniantz G, Dahimene S, Becq F, Merot J, Gauthier C
NHE-RF1 protein rescues DeltaF508-CFTR function.
American journal of physiology. Lung cellular and molecular physiology 2007 May;292(5):L1085-94