Distinct proteostasis states drive pharmacologic chaperone susceptibility for cystic fibrosis transmembrane conductance regulator misfolding mutants
Eli Fritz McDonald, Carleen Mae P. Sabusap, Min‐Soo Kim, Lars Plate
Abstract
mutations P67L and L206W exhibit decreased interactions with proteasomal and autophagy degradation machinery compared with F508del and G85E. We then show inhibiting the proteasome attenuates P67L and L206W VX-809 response. Our data suggest a previously unidentified but required role for protein degradation in VX-809 correction. Furthermore, we present an approach for identifying proteostasis characteristics of mutant-specific therapeutic response to pharmacological chaperones.
Topics & Concepts
ProteostasisCystic fibrosis transmembrane conductance regulatorBiologyRegulatorCystic fibrosisMutantCell biologyChaperone (clinical)Negative regulatorTransmembrane proteinProtein foldingGeneticsSignal transductionPathologyGeneMedicineReceptorCystic Fibrosis Research AdvancesBacterial Genetics and BiotechnologyCellular transport and secretion