Abstract
Background: Many genetic diseases are due to defects in protein trafficking where the mutant protein is recognized by the quality control systems, retained in the endoplasmic reticulum (ER), and degraded by the proteasome. In many cases, the mutant protein retains function if it can be trafficked to its proper cellular location. We have identified structurally diverse correctors that restore the trafficking and function of the most common mutation causing cystic fibrosis, F508del-CFTR. Most of these correctors do not act directly as ligands of CFTR, but indirectly on other pathways to promote folding and correction. We hypothesize that these proteostasis regulators may also correct other protein trafficking diseases. Methods: To test our hypothesis, we used stable cell lines or transient transfection to express 2 well-studied trafficking disease mutations in each of 3 different proteins: the arginine-vasopressin receptor 2 (AVPR2, also known as V2R), the human ether-a-go-go-related gene (KCNH2, also known as hERG), and finally the sulfonylurea receptor 1 (ABCC8, also known as SUR1). We treated cells expressing these mutant proteins with 9 structurally diverse F508del-CFTR correctors that function through different cellular mechanisms and assessed whether correction occurred via immunoblotting and functional assays. Results were deemed significantly different from controls by a one-way ANOVA (p <0.05). Results: Here we show that F508del-CFTR correctors RDR1, KM60 and KM57 also correct some mutant alleles of other protein trafficking diseases. We also show that one corrector, the cardiac glycoside ouabain, was found to alter the glycosylation of all mutant alleles tested. Conclusions: Correctors of F508del-CFTR trafficking might have broader applications to other protein trafficking diseases.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 11 |
| Number of pages | 1 |
| Journal | Orphanet Journal of Rare Diseases |
| DOIs | |
| State | Accepted/In press - Jan 14 2013 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Pharmacology (medical)
- Genetics(clinical)
- Medicine(all)
Cite this
Compounds that correct F508del-CFTR trafficking can also correct other protein trafficking diseases : An in vitro study using cell lines. / Sampson, Heidi M.; Lam, Hung; Chen, Pei Chun; Zhang, Donglei; Mottillo, Cristina; Mirza, Myriam; Qasim, Karim; Shrier, Alvin; Shyng, Show-Ling; Hanrahan, John W.; Thomas, David Y.
In: Orphanet Journal of Rare Diseases, 14.01.2013, p. 11.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Compounds that correct F508del-CFTR trafficking can also correct other protein trafficking diseases
T2 - An in vitro study using cell lines
AU - Sampson, Heidi M.
AU - Lam, Hung
AU - Chen, Pei Chun
AU - Zhang, Donglei
AU - Mottillo, Cristina
AU - Mirza, Myriam
AU - Qasim, Karim
AU - Shrier, Alvin
AU - Shyng, Show-Ling
AU - Hanrahan, John W.
AU - Thomas, David Y.
PY - 2013/1/14
Y1 - 2013/1/14
N2 - Background: Many genetic diseases are due to defects in protein trafficking where the mutant protein is recognized by the quality control systems, retained in the endoplasmic reticulum (ER), and degraded by the proteasome. In many cases, the mutant protein retains function if it can be trafficked to its proper cellular location. We have identified structurally diverse correctors that restore the trafficking and function of the most common mutation causing cystic fibrosis, F508del-CFTR. Most of these correctors do not act directly as ligands of CFTR, but indirectly on other pathways to promote folding and correction. We hypothesize that these proteostasis regulators may also correct other protein trafficking diseases. Methods: To test our hypothesis, we used stable cell lines or transient transfection to express 2 well-studied trafficking disease mutations in each of 3 different proteins: the arginine-vasopressin receptor 2 (AVPR2, also known as V2R), the human ether-a-go-go-related gene (KCNH2, also known as hERG), and finally the sulfonylurea receptor 1 (ABCC8, also known as SUR1). We treated cells expressing these mutant proteins with 9 structurally diverse F508del-CFTR correctors that function through different cellular mechanisms and assessed whether correction occurred via immunoblotting and functional assays. Results were deemed significantly different from controls by a one-way ANOVA (p <0.05). Results: Here we show that F508del-CFTR correctors RDR1, KM60 and KM57 also correct some mutant alleles of other protein trafficking diseases. We also show that one corrector, the cardiac glycoside ouabain, was found to alter the glycosylation of all mutant alleles tested. Conclusions: Correctors of F508del-CFTR trafficking might have broader applications to other protein trafficking diseases.
AB - Background: Many genetic diseases are due to defects in protein trafficking where the mutant protein is recognized by the quality control systems, retained in the endoplasmic reticulum (ER), and degraded by the proteasome. In many cases, the mutant protein retains function if it can be trafficked to its proper cellular location. We have identified structurally diverse correctors that restore the trafficking and function of the most common mutation causing cystic fibrosis, F508del-CFTR. Most of these correctors do not act directly as ligands of CFTR, but indirectly on other pathways to promote folding and correction. We hypothesize that these proteostasis regulators may also correct other protein trafficking diseases. Methods: To test our hypothesis, we used stable cell lines or transient transfection to express 2 well-studied trafficking disease mutations in each of 3 different proteins: the arginine-vasopressin receptor 2 (AVPR2, also known as V2R), the human ether-a-go-go-related gene (KCNH2, also known as hERG), and finally the sulfonylurea receptor 1 (ABCC8, also known as SUR1). We treated cells expressing these mutant proteins with 9 structurally diverse F508del-CFTR correctors that function through different cellular mechanisms and assessed whether correction occurred via immunoblotting and functional assays. Results were deemed significantly different from controls by a one-way ANOVA (p <0.05). Results: Here we show that F508del-CFTR correctors RDR1, KM60 and KM57 also correct some mutant alleles of other protein trafficking diseases. We also show that one corrector, the cardiac glycoside ouabain, was found to alter the glycosylation of all mutant alleles tested. Conclusions: Correctors of F508del-CFTR trafficking might have broader applications to other protein trafficking diseases.
UR - http://www.scopus.com/inward/record.url?scp=84872122357&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84872122357&partnerID=8YFLogxK
U2 - 10.1186/1750-1172-8-11
DO - 10.1186/1750-1172-8-11
M3 - Article
C2 - 23316740
AN - SCOPUS:84872122357
SP - 11
JO - Orphanet Journal of Rare Diseases
JF - Orphanet Journal of Rare Diseases
SN - 1750-1172
ER -