Compounds that correct F508del-CFTR trafficking can also correct other protein trafficking diseases: an in vitro study using cell lines

Orphanet Journal of Rare Diseases

David Y Thomas¹  John W Hanrahan²  Show-Ling Shyng³  Alvin Shrier²  Karim Qasim¹  Myriam Mirza¹  Cristina Mottillo¹  Donglei Zhang¹  Pei-Chun Chen³  Hung Lam²  Heidi M Sampson¹ 

[1] Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, McIntyre Medical Building, Montréal, Québec H3G 1Y6, Canada;Department of Physiology, McGill University, 3655 Promenade Sir William Osler, McIntyre Medical Building, Montréal, Québec H3G 1Y6, Canada;Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Mail Stop L224, 3181S.W. Sam Jackson Park Road, Portland, OR, 97239-3098, USA

关键词: SUR1;    ABCC8;    V2R;    AVPR2;    KCNH2;    hERG;    CFTR;    Proteostasis;    Corrector;    Protein trafficking;   

Others  :  864142
DOI  :  10.1186/1750-1172-8-11

 received in 2012-08-21, accepted in 2013-01-01,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Sampson et al.; licensee BioMed Central Ltd.

【 图 表 】

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