scholarly journals Cystic Fibrosis Transmembrane Conductance Regulator Degradation Depends on the Lectins Htm1p/EDEM and the Cdc48 Protein Complex in Yeast

2004 ◽  
Vol 15 (9) ◽  
pp. 4125-4135 ◽  
Author(s):  
Andreas Gnann ◽  
John R. Riordan ◽  
Dieter H. Wolf
Keyword(s):  
Cystic Fibrosis ◽  
Quality Control ◽  
Protein Quality ◽  
Hereditary Disease ◽  
Yeast Cells ◽  
Common Mutation ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Yeast Saccharomyces Cerevisiae ◽  
Cystic Fibrosis Transmembrane

Cystic fibrosis is the most widespread hereditary disease among the white population caused by different mutations of the apical membrane ATP-binding cassette transporter cystic fibrosis transmembrane conductance regulator (CFTR). Its most common mutation, ΔF508, leads to nearly complete degradation via endoplasmic reticulum-associated degradation (ERAD). Elucidation of the quality control and degradation mechanisms might give rise to new therapeutic approaches to cure this disease. In the yeast Saccharomyces cerevisiae, a variety of components of the protein quality control and degradation system have been identified. Nearly all of these components share homology with mammalian counterparts. We therefore used yeast mutants defective in the ERAD system to identify new components that are involved in human CFTR quality control and degradation. We show the role of the lectin Htm1p in the degradation process of CFTR. Complementation of the HTM1 deficiency in yeast cells by the mammalian orthologue EDEM underlines the necessity of this lectin for CFTR degradation and highlights the similarity of quality control and ERAD in yeast and mammals. Furthermore, degradation of CFTR requires the ubiquitin protein ligases Der3p/Hrd1p and Doa10p as well as the cytosolic trimeric Cdc48p-Ufd1p-Npl4p complex. These proteins also were found to be necessary for ERAD of a mutated yeast “relative” of CFTR, Pdr5*p.

scholarly journals The Cochaperone HspBP1 Inhibits the CHIP Ubiquitin Ligase and Stimulates the Maturation of the Cystic Fibrosis Transmembrane Conductance Regulator

2004 ◽  
Vol 15 (9) ◽  
pp. 4003-4010 ◽  
Author(s):  
Simon Alberti ◽  
Karsten Böhse ◽  
Verena Arndt ◽  
Anton Schmitz ◽  
Jörg Höhfeld
Keyword(s):  
Cystic Fibrosis ◽  
Quality Control ◽  
Ubiquitin Ligase ◽  
Molecular Chaperones ◽  
Protein Quality ◽  
Regulatory Mechanism ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Ubiquitin Ligase Activity ◽  
Cystic Fibrosis Transmembrane

The CHIP ubiquitin ligase turns molecular chaperones into protein degradation factors. CHIP associates with the chaperones Hsc70 and Hsp90 during the regulation of signaling pathways and during protein quality control, and directs chaperone-bound clients to the proteasome for degradation. Obviously, this destructive activity should be carefully controlled. Here, we identify the cochaperone HspBP1 as 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 of the cystic fibrosis transmembrane conductance regulator (CFTR) and stimulates CFTR maturation. Our data reveal a novel regulatory mechanism that determines folding and degradation activities of molecular chaperones.

scholarly journals Role of transmembrane spanning domain 1 in cystic fibrosis transmembrane conductance regulator folding

2021 ◽  
Author(s):  
Anna E. Patrick ◽  
Linda Millen ◽  
Philip J. Thomas
Keyword(s):  
Cystic Fibrosis ◽  
Transient Stability ◽  
Protein Quality ◽  
Regulatory Region ◽  
Common Mutation ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Binding Domains ◽  
The Impact ◽  
Cystic Fibrosis Transmembrane

AbstractCystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein that disrupt its folding pathway. The most common mutation causing CF is a deletion of phenylalanine at position 508 (ΔF508). CFTR contains five domains that each form cotranslational structures that interact with other domains as they are produced and folded. CFTR is comprised of two transmembrane spanning domains (TMDs), two nucleotide binding domains (NBDs) and a unique regulatory region (R). The first domain translated, TMD1, forms interdomain interactions with the other domains in CFTR. In TMD1, long intracellular loops extend into the cytoplasm and interact with both NBDs via coupling helices and with TMD2 via transmembrane spans (TMs). We examined mutations in TMD1 to determine the impact on individual domain and multidomain constructs. We found that mutations in a TM span or in the cytosolic ICLs interfere with specific steps in the hierarchical folding of CFTR. TM1 CF-causing mutants, G85E and G91R, directly affect TMD1, whereas most ICL1 and ICL2 mutant effects become apparent in the presence of TMD2. A single mutant in ICL2 worsened CFTR trafficking in the presence of NBD2, supporting its role in the ICL2-NBD2 interface. Mutation of hydrophobic residues in ICL coupling helices tended to increased levels of pre-TMD2 biogenic intermediates but caused ER accumulation in the presence of TMD2. This suggests a tradeoff between transient stability during translation and final structure. NBD2 increased the efficiency of mutant trafficking from the ER, consistent with stabilization of the full-length constructs. While the G85E and G91R mutants in TM1 have immediately detectable effects, most of the studied mutant effects and the ΔF508 mutant are apparent after production of TMD2, supporting this intermediate as a major point of recognition by protein quality control.

scholarly journals The endoplasmic reticulum–associated Hsp40 DNAJB12 and Hsc70 cooperate to facilitate RMA1 E3–dependent degradation of nascent CFTRΔF508

2011 ◽  
Vol 22 (3) ◽  
pp. 301-314 ◽  
Author(s):  
Diane E. Grove ◽  
Chun-Yang Fan ◽  
Hong Yu Ren ◽  
Douglas M. Cyr
Keyword(s):  
Cystic Fibrosis ◽  
Endoplasmic Reticulum ◽  
Protein Quality ◽  
Transmembrane Conductance Regulator ◽  
Folding Kinetics ◽  
Transmembrane Conductance ◽  
Life And Death ◽  
Native Proteins ◽  
Versus Protein ◽  
Cystic Fibrosis Transmembrane

Relative contributions of folding kinetics versus protein quality control (QC) activity in the partitioning of non-native proteins between life and death are not clear. Cystic fibrosis transmembrane conductance regulator (CFTR) biogenesis serves as an excellent model to study this question because folding of nascent CFTR is inefficient and deletion of F508 causes accumulation of CFTRΔF508 in a kinetically trapped, but foldable state. Herein, a novel endoplasmic reticulum (ER)-associated Hsp40, DNAJB12 (JB12) is demonstrated to play a role in control of CFTR folding efficiency. JB12 cooperates with cytosolic Hsc70 and the ubiquitin ligase RMA1 to target CFTR and CFTRΔF508 for degradation. Modest elevation of JB12 decreased nascent CFTR and CFTRΔF508 accumulation while increasing association of Hsc70 with ER forms of CFTR and the RMA1 E3 complex. Depletion of JB12 increased CFTR folding efficiency up to threefold and permitted a pool of CFTRΔF508 to fold and escape the ER. Introduction of the V510D misfolding suppressor mutation into CFTRΔF508 modestly increased folding efficiency, whereas combined inactivation of JB12 and suppression of intrinsic folding defects permitted CFTRΔF508 to fold at 50% of wild-type efficiency. Therapeutic correction of CFTRΔF508 misfolding in cystic fibrosis patients may require repair of defective folding kinetics and suppression of ER QC factors, such as JB12.

scholarly journals Sequential Quality-Control Checkpoints Triage Misfolded Cystic Fibrosis Transmembrane Conductance Regulator

Cell ◽  
2006 ◽  
Vol 126 (3) ◽  
pp. 571-582 ◽  
Author(s):  
J. Michael Younger ◽  
Liling Chen ◽  
Hong-Yu Ren ◽  
Meredith F.N. Rosser ◽  
Emma L. Turnbull ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Quality Control ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Cystic Fibrosis Transmembrane

scholarly journals Stress activated MAPK influence the quality control of misfolded cystic fibrosis transmembrane conductance regulator.

2013 ◽  
Vol 27 (S1) ◽  
Author(s):  
Ramanath Narayana Hegde ◽  
Seetharaman Parashuraman ◽  
Francesco Iorio ◽  
Diego Di Bernardo ◽  
Alberto Luini
Keyword(s):  
Cystic Fibrosis ◽  
Quality Control ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Cystic Fibrosis Transmembrane

scholarly journals COPII-dependent export of cystic fibrosis transmembrane conductance regulator from the ER uses a di-acidic exit code

2004 ◽  
Vol 167 (1) ◽  
pp. 65-74 ◽  
Author(s):  
Xiaodong Wang ◽  
Jeanne Matteson ◽  
Yu An ◽  
Bryan Moyer ◽  
Jin-San Yoo ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Hereditary Disease ◽  
Mutant Form ◽  
Transmembrane Conductance Regulator ◽  
Wild Type ◽  
Transmembrane Conductance ◽  
Primary Defect ◽  
Cf Transmembrane Conductance Regulator ◽  
Er Export ◽  
Cystic Fibrosis Transmembrane

Cystic fibrosis (CF) is a childhood hereditary disease in which the most common mutant form of the CF transmembrane conductance regulator (CFTR) ΔF508 fails to exit the endoplasmic reticulum (ER). Export of wild-type CFTR from the ER requires the coat complex II (COPII) machinery, as it is sensitive to Sar1 mutants that disrupt normal coat assembly and disassembly. In contrast, COPII is not used to deliver CFTR to ER-associated degradation. We find that exit of wild-type CFTR from the ER is blocked by mutation of a consensus di-acidic ER exit motif present in the first nucleotide binding domain. Mutation of the code disrupts interaction with the COPII coat selection complex Sec23/Sec24. We propose that the di-acidic exit code plays a key role in linking CFTR to the COPII coat machinery and is the primary defect responsible for CF in ΔF508-expressing patients.

scholarly journals An Overview of the Homozygous Cystic Fibrosis Transmembrane Conductance Regulator Mutation c.3700 A>G (p.Ile1234Val) in Qatar

2019 ◽  
Vol 7 (4) ◽  
pp. 187-190
Author(s):  
Samer Hammoudeh ◽  
Wessam Gadelhak ◽  
Atqah AbdulWahab ◽  
Mona Al-Langawi ◽  
Ibrahim A. Janahi
Keyword(s):  
Cystic Fibrosis ◽  
Arabian Gulf ◽  
Future Research ◽  
Common Mutation ◽  
Activity Levels ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Gulf Region ◽  
Research Activities ◽  
Cystic Fibrosis Transmembrane

Abstract Purpose of Review Cystic fibrosis (CF) is a monogenic recessive disease with multisystem involvement. The cause is a mutation in the gene that encodes the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The aim is to review the literature involving the CFTR I1234V mutation and to provide recommendations for future research activities. Recent Findings The prevalence rates of CFTR mutations vary across the globe. The CFTR I1234V mutation is the most common mutation in Qatar, and one of the most common in the Arabian Gulf region. Summary Areas for future research include testing of the CFTR transcript and activity levels in different samples including nasal cells and organoids. Another area is applying Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technology as a tool for gene editing.

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