CFTR F508del binds components of the ERAD machinery for ubiquitination and degradation

Stable Identifier
Reaction [binding]
Homo sapiens
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Deletion of phenylalanine 508 in CFTR is the most prevalent mutation causing cystic fibrosis (Riordan et al, 1989; Kerem et al, 1989). F508 deletion causes destabilization and subsequent targeting for co-translational degradation by the ER-associated degradation machinery (ERAD). Like misfolded WT CFTR protein, F508del is ubiquitinated by ERAD-associated E3 ligases including RNF5 and RNF 185, targeting it for VCP-mediated retrotranslocation and 26S proteasomal degradation (Meachem et al, 2001; Rosser et al, 2008; Younger et al, 2004; Younger et al, 2006; El Khouri et al, 2013; reviewed in Pranke and Sermet-Gaudelus, 2014).
Literature References
PubMed ID Title Journal Year
24019521 RNF185 is a novel E3 ligase of endoplasmic reticulum-associated degradation (ERAD) that targets cystic fibrosis transmembrane conductance regulator (CFTR)

El Khouri, E, Toledano, MB, Le Pavec, G, Delaunay-Moisan, A

J. Biol. Chem. 2013
15611333 A foldable CFTR{Delta}F508 biogenic intermediate accumulates upon inhibition of the Hsc70-CHIP E3 ubiquitin ligase

Fields, A, Fan, CY, Ren, HY, Younger, JM, Cyr, DM, Chen, L, Patterson, C

J. Cell Biol. 2004
16901789 Sequential quality-control checkpoints triage misfolded cystic fibrosis transmembrane conductance regulator

Fan, CY, Ren, HY, Rosser, MF, Younger, JM, Cyr, DM, Turnbull, EL, Chen, L, Patterson, C

Cell 2006
18716059 Assembly and misassembly of cystic fibrosis transmembrane conductance regulator: folding defects caused by deletion of F508 occur before and after the calnexin-dependent association of membrane spanning domain (MSD) 1 and MSD2

Grove, DE, Rosser, MF, Cyr, DM, Chen, L

Mol. Biol. Cell 2008
2475911 Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA

Chou, JL, Alon, N, Kerem, B, Riordan, JR, Rozmahel, R, Plavsic, N, Grzelczak, Z, Lok, S, Zielenski, J, Rommens, JM

Science 1989
11146634 The Hsc70 co-chaperone CHIP targets immature CFTR for proteasomal degradation

Meacham, GC, Younger, JM, Zhang, W, Cyr, DM, Patterson, C

Nat. Cell Biol. 2001
24685677 Biosynthesis of cystic fibrosis transmembrane conductance regulator

Sermet-Gaudelus, I, Pranke, IM

Int. J. Biochem. Cell Biol. 2014
2570460 Identification of the cystic fibrosis gene: genetic analysis

Markiewicz, D, Buchanan, JA, Buchwald, M, Kerem, B, Cox, TK, Tsui, LC, Chakravarti, A, Rommens, JM

Science 1989
Normal reaction
Functional status

Gain of function of CFTR F508del [endoplasmic reticulum membrane]

Name Identifier Synonyms
cystic fibrosis DOID:1485 mucoviscidosis, CF
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