Pathway maps

Regulation of degradation of wt-CFTR
Regulation of degradation of wt-CFTR

Object List (links open in MetaCore):

Derlin1, HSC70, CHIP, HSPBP1, UBE2D1, BAG-2, UFD1, SEC61 complex, MJD (ataxin-3), NPL4, Csp, RNF5, UBE2J1, CFTR, Ubiquitin, UBE1, 26S proteasome (20S core), CFTR, VCP, CFTR

Description

Regulation of degradation of wt-CFTR (norm)

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].

Ubiquitin-proteasome-mediated degradation is the key pathway in wt-CFTR regulation [6], [7], [8], [9].

Two ubiquitin ligase complexes mark wt-CFTR for degradation - ER ubiquitin ligase complex and cytosolic ubiquitin ligase complex. The first complex (ER membrane-associated ubiquitin ligase complex) contains the E3 RMA1 ( RNF5 ), the E2 Ubc6e ( UNE2J1 ), and Derlin-1. Derlin-1 interacts with nonubiquitylated CFTR and serves to retain CFTR in the ER membrane [10], [11].

The second complex (cytosolic ubiquitin ligase complex) contains E3 CHIP, UBCH5a and acts in Hsc70 [12], [10].

Cochaperone HspBP1 is an inhibitor of CHIP. HspBP1 attenuates the ubiquitin ligase activity of CHIP when complexed with Hsc70. As a consequence, HspBP1 interferes with the CHIP-induced degradation of immature forms and may modulate the function of the Hsc70/CHIP complex [13].

Csp ( DnaJ (Hsp40) homolog, subfamily C, member 5) , blocks ER exit of wt-CFTR. Additionally, Csp associates with CHIP and facilitates degradation of immature wt-CFTR (Schmidt, B. unpublished data, The 21 st Annual North American CF conference Anaheim Convention Center, Anaheim, California, October 3-6, 2007}

The ubiquitylated wt-CFTR is transported through the Sec61 trimeric complex back to the cytosol, escorted by the beta subunit of Sec61 [14].

VCP/p97, a Type II AAA ATPase component of the retrotranslocation machinery, forms a complex with substrate-recruiting cofactors Ufd1/Npl4. VCP binds polyubiquinated wt-CFTR while Ufd1/Npl4 interacts to the ubiquitin chains on the substrate [15], [9]. VCP activity may be regulated by Ataxin-3 [16].

In situations where 26S proteasome are compromised or overwhelmed, ubiquitinated misfolded wt-CFTR is transported to a perinuclear location near the microtubule-organizing center to form aggresomes [17], [18].

References:

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    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. Ward CL, Omura S, Kopito RR
    Degradation of CFTR by the ubiquitin-proteasome pathway. Cell 1995 Oct 6;83(1):121-7
  7. Jensen TJ, Loo MA, Pind S, Williams DB, Goldberg AL, Riordan JR
    Multiple proteolytic systems, including the proteasome, contribute to CFTR processing. Cell 1995 Oct 6;83(1):129-35
  8. Gelman MS, Kannegaard ES, Kopito RR
    A principal role for the proteasome in endoplasmic reticulum-associated degradation of misfolded intracellular cystic fibrosis transmembrane conductance regulator. The Journal of biological chemistry 2002 Apr 5;277(14):11709-14
  9. Goldstein RF, Niraj A, Sanderson TP, Wilson LS, Rab A, Kim H, Bebok Z, Collawn JF
    VCP/p97 AAA-ATPase Does not Interact with the Endogenous Wild-Type CFTR. American journal of respiratory cell and molecular biology 2007 Feb 8;
  10. Younger JM, Chen L, Ren HY, Rosser MF, Turnbull EL, Fan CY, Patterson C, Cyr DM
    Sequential quality-control checkpoints triage misfolded cystic fibrosis transmembrane conductance regulator. Cell 2006 Aug 11;126(3):571-82
  11. Sun F, Zhang R, Gong X, Geng X, Drain PF, Frizzell RA
    Derlin-1 Promotes the Efficient Degradation of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) and CFTR Folding Mutants. The Journal of biological chemistry 2006 Dec 1;281(48):36856-63
  12. Jiang J, Ballinger CA, Wu Y, Dai Q, Cyr DM, Hohfeld J, Patterson C
    CHIP is a U-box-dependent E3 ubiquitin ligase: identification of Hsc70 as a target for ubiquitylation. The Journal of biological chemistry 2001 Nov 16;276(46):42938-44
  13. Alberti S, Bohse K, Arndt V, Schmitz A, Hohfeld J
    The cochaperone HspBP1 inhibits the CHIP ubiquitin ligase and stimulates the maturation of the cystic fibrosis transmembrane conductance regulator. Molecular biology of the cell 2004 Sep;15(9):4003-10
  14. Bebok Z, Mazzochi C, King SA, Hong JS, Sorscher EJ
    The mechanism underlying cystic fibrosis transmembrane conductance regulator transport from the endoplasmic reticulum to the proteasome includes Sec61beta and a cytosolic, deglycosylated intermediary. The Journal of biological chemistry 1998 Nov 6;273(45):29873-8
  15. Gnann A, Riordan JR, Wolf DH
    Cystic fibrosis transmembrane conductance regulator degradation depends on the lectins Htm1p/EDEM and the Cdc48 protein complex in yeast. Molecular biology of the cell 2004 Sep;15(9):4125-35
  16. Zhong X, Pittman RN
    Ataxin-3 binds VCP/p97 and regulates retrotranslocation of ERAD substrates. Human molecular genetics 2006 Aug 15;15(16):2409-20
  17. Johnston JA, Ward CL, Kopito RR
    Aggresomes: a cellular response to misfolded proteins. The Journal of cell biology 1998 Dec 28;143(7):1883-98
  18. Turnbull EL, Rosser MF, Cyr DM
    The role of the UPS in cystic fibrosis. BMC biochemistry 2007 Nov 22;8 Suppl 1:S11