Matches in SemOpenAlex for { <https://semopenalex.org/work/W4386575199> ?p ?o ?g. }
- W4386575199 endingPage "105242" @default.
- W4386575199 startingPage "105242" @default.
- W4386575199 abstract "Cystic fibrosis (CF) is one of the most prevalent lethal genetic diseases with over 2000 identified mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Pharmacological chaperones such as Lumacaftor (VX-809), Tezacaftor (VX-661) and Elexacaftor (VX-445) treat mutation-induced defects by stabilizing CFTR and are called correctors. These correctors improve proper folding and thus facilitate processing and trafficking to increase the amount of functional CFTR on the cell surface. Yet, CFTR variants display differential responses to each corrector. Here, we report variants P67L and L206W respond similarly to VX-809 but divergently to VX-445 with P67L exhibiting little rescue when treated with VX-445. We investigate the underlying cellular mechanisms of how CFTR biogenesis is altered by correctors in these variants. Affinity purification-mass spectrometry (AP-MS) multiplexed with isobaric Tandem Mass Tags (TMT) was used to quantify CFTR protein-protein interaction changes between variants P67L and L206W. VX-445 facilitates unique proteostasis factor interactions especially in translation, folding, and degradation pathways in a CFTR variant-dependent manner. A number of these interacting proteins knocked down by siRNA, such as ribosomal subunit proteins, moderately rescued fully glycosylated P67L. Importantly, these knockdowns sensitize P67L to VX-445 and further enhance the trafficking correction of this variant. Partial inhibition of protein translation also mildly sensitizes P67L CFTR to VX-445 correction, supporting a role for translational dynamics in the rescue mechanism of VX-445. Our results provide a better understanding of VX-445 biological mechanism of action and reveal cellular targets that may sensitize unresponsive CFTR variants to known and available correctors." @default.
- W4386575199 created "2023-09-10" @default.
- W4386575199 creator A5004507009 @default.
- W4386575199 creator A5008487059 @default.
- W4386575199 creator A5020241831 @default.
- W4386575199 creator A5024304493 @default.
- W4386575199 creator A5044846698 @default.
- W4386575199 creator A5050704941 @default.
- W4386575199 creator A5054547248 @default.
- W4386575199 creator A5083612212 @default.
- W4386575199 creator A5091626287 @default.
- W4386575199 date "2023-10-01" @default.
- W4386575199 modified "2023-10-18" @default.
- W4386575199 title "Elexacaftor/VX-445-mediated CFTR interactome remodeling reveals differential correction driven by mutation-specific translational dynamics" @default.
- W4386575199 cites W1520171546 @default.
- W4386575199 cites W1524641046 @default.
- W4386575199 cites W1969697265 @default.
- W4386575199 cites W1976507289 @default.
- W4386575199 cites W1979411632 @default.
- W4386575199 cites W1986304086 @default.
- W4386575199 cites W2004155358 @default.
- W4386575199 cites W2008559063 @default.
- W4386575199 cites W2015357935 @default.
- W4386575199 cites W2036961764 @default.
- W4386575199 cites W2048373373 @default.
- W4386575199 cites W2071407356 @default.
- W4386575199 cites W2079610466 @default.
- W4386575199 cites W2080044891 @default.
- W4386575199 cites W2095617700 @default.
- W4386575199 cites W2111868411 @default.
- W4386575199 cites W2113570557 @default.
- W4386575199 cites W2116511323 @default.
- W4386575199 cites W2118445531 @default.
- W4386575199 cites W2125639616 @default.
- W4386575199 cites W2139839186 @default.
- W4386575199 cites W2139873559 @default.
- W4386575199 cites W2150318917 @default.
- W4386575199 cites W2151837778 @default.
- W4386575199 cites W2154663605 @default.
- W4386575199 cites W2157295566 @default.
- W4386575199 cites W2158758026 @default.
- W4386575199 cites W2166608358 @default.
- W4386575199 cites W2167844024 @default.
- W4386575199 cites W2170032136 @default.
- W4386575199 cites W2188967200 @default.
- W4386575199 cites W2348038189 @default.
- W4386575199 cites W2507455186 @default.
- W4386575199 cites W2554771791 @default.
- W4386575199 cites W2609484639 @default.
- W4386575199 cites W2618831618 @default.
- W4386575199 cites W2734356283 @default.
- W4386575199 cites W2792910868 @default.
- W4386575199 cites W2795911726 @default.
- W4386575199 cites W2808931713 @default.
- W4386575199 cites W2839995495 @default.
- W4386575199 cites W2883731211 @default.
- W4386575199 cites W2884228015 @default.
- W4386575199 cites W2897626245 @default.
- W4386575199 cites W2900751195 @default.
- W4386575199 cites W2914729923 @default.
- W4386575199 cites W2937022217 @default.
- W4386575199 cites W2947765278 @default.
- W4386575199 cites W2952096628 @default.
- W4386575199 cites W2982222494 @default.
- W4386575199 cites W2982296199 @default.
- W4386575199 cites W2982694109 @default.
- W4386575199 cites W2998769044 @default.
- W4386575199 cites W2998785333 @default.
- W4386575199 cites W3008025512 @default.
- W4386575199 cites W3013565341 @default.
- W4386575199 cites W3021805472 @default.
- W4386575199 cites W3029824713 @default.
- W4386575199 cites W3037656689 @default.
- W4386575199 cites W3081438953 @default.
- W4386575199 cites W3081492719 @default.
- W4386575199 cites W3099364488 @default.
- W4386575199 cites W3108269660 @default.
- W4386575199 cites W3147967992 @default.
- W4386575199 cites W3149437330 @default.
- W4386575199 cites W3181000983 @default.
- W4386575199 cites W3204156393 @default.
- W4386575199 cites W3208691473 @default.
- W4386575199 cites W3208893265 @default.
- W4386575199 cites W4200089256 @default.
- W4386575199 cites W4200545083 @default.
- W4386575199 cites W4205602647 @default.
- W4386575199 cites W4225615972 @default.
- W4386575199 cites W4226085625 @default.
- W4386575199 cites W4229660611 @default.
- W4386575199 cites W4241884576 @default.
- W4386575199 cites W4306895629 @default.
- W4386575199 cites W4378714741 @default.
- W4386575199 doi "https://doi.org/10.1016/j.jbc.2023.105242" @default.
- W4386575199 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/37690692" @default.
- W4386575199 hasPublicationYear "2023" @default.
- W4386575199 type Work @default.
- W4386575199 citedByCount "0" @default.
- W4386575199 crossrefType "journal-article" @default.