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

• DOI: 10.1186/1750-1172-8-11
• Publication Date: 2013-01-14T17:14:09Z
• Authors: Heidi M Sampson; Hung Lam; Pei-Chun Chen; Donglei Zhang; Cristina Mottillo; Myriam Mirza; Karim Qasim; Alvin Shrier; Show-Ling Shyng; John W Hanrahan; David Y Thomas
• Keywords: Mutant protein; Transport protein; Proteostasis; Endoplasmic-reticulum-associated protein degradation; Synthetic Lethality

Abstract Background Many genetic diseases are due to defects in protein trafficking where the mutant is recognized by quality control systems, retained endoplasmic reticulum (ER), and degraded proteasome. In many cases, retains function if it can be trafficked its proper cellular location. We have identified structurally diverse correctors that restore of most common mutation causing cystic fibrosis, F508del-CFTR. Most these do not act directly as ligands CFTR, but indirectly on other pathways promote folding correction. hypothesize proteostasis regulators may also correct diseases. Methods To test our hypothesis, we used stable cell lines or transient transfection express 2 well-studied disease mutations each 3 different proteins: arginine-vasopressin receptor (AVPR2, known V2R), human ether-a-go-go-related gene (KCNH2, hERG), finally sulfonylurea 1 (ABCC8, SUR1). treated cells expressing proteins with 9 F508del-CFTR through mechanisms assessed whether correction occurred via immunoblotting functional assays. Results were deemed significantly from controls a one-way ANOVA ( p < 0.05). Here show RDR1, KM60 KM57 some alleles one corrector, cardiac glycoside ouabain, was found alter glycosylation all tested. Conclusions Correctors might broader applications