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The cystic fibrosis-associated ΔF508 mutation confers post-transcriptional destabilization on the C. elegans ABC transporter PGP-3
- Source :
- Disease Models & Mechanisms, Vol 5, Iss 6, Pp 930-939 (2012), Disease Models & Mechanisms
- Publication Year :
- 2012
- Publisher :
- The Company of Biologists, 2012.
-
Abstract
- Summary Membrane proteins comprise ~30% of the proteome. During the early stages of maturation, this class of proteins can experience localized misfolding in distinct cellular compartments, such as the cytoplasm, endoplasmic reticulum (ER) lumen, and ER membrane. ER quality control (ERQC) mechanisms monitor folding and determine whether a membrane protein is appropriately folded or is misfolded and warrants degradation. ERQC plays critical roles in human diseases, such as cystic fibrosis, where deletion of a single amino acid (F508) results in the misfolding and degradation of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Cl- channel. We introduced the ΔF508 mutation into C. elegans PGP-3, a 12 transmembrane ABC transporter with 15% identity to CFTR. When expressed in intestinal epithelial cells, PGP-3wt was stable and efficiently trafficked to the apical plasma membrane through a COPII-dependent mechanism. However, PGP-3ΔF508 was post-transcriptionally destabilized, resulting in reduced total and apical membrane protein levels. Genetic or physiological activation of the osmotic stress response pathway, which causes accumulation of the chemical chaperone glycerol, stabilized PGP-3ΔF508. Efficient degradation of PGP-3ΔF508 required the function of several C. elegans endoplasmic reticulum-associated degradation (ERAD) homologs, suggesting that destabilization occurs through an ERAD-type mechanism. Our studies show that the ΔF508 mutation causes post-transcriptional destabilization and degradation of PGP-3 in C. elegans epithelial cells. This model, combined with the power of C. elegans genetics, provides a new opportunity to genetically dissect metazoan ERQC.
- Subjects :
- Research Report
ATP Binding Cassette Transporter, Subfamily B
Cystic Fibrosis
Transcription, Genetic
Neuroscience (miscellaneous)
Cystic Fibrosis Transmembrane Conductance Regulator
lcsh:Medicine
Medicine (miscellaneous)
ATP-binding cassette transporter
Endoplasmic-reticulum-associated protein degradation
General Biochemistry, Genetics and Molecular Biology
03 medical and health sciences
0302 clinical medicine
Immunology and Microbiology (miscellaneous)
Osmotic Pressure
Stress, Physiological
lcsh:Pathology
Animals
Humans
Caenorhabditis elegans
Caenorhabditis elegans Proteins
ΔF508
030304 developmental biology
0303 health sciences
biology
Protein Stability
Endoplasmic reticulum
Cell Membrane
lcsh:R
Cell Polarity
Endoplasmic Reticulum-Associated Degradation
Apical membrane
Cystic fibrosis transmembrane conductance regulator
Cell biology
Membrane protein
Gene Knockdown Techniques
Mutation
biology.protein
ATP-Binding Cassette Transporters
Chemical chaperone
030217 neurology & neurosurgery
lcsh:RB1-214
Subjects
Details
- ISSN :
- 17548411 and 17548403
- Database :
- OpenAIRE
- Journal :
- Disease Models & Mechanisms
- Accession number :
- edsair.doi.dedup.....44d3658e4b940af78767fb99362a2d74