Ribosomal Stalk Protein Silencing Partially Corrects the ?F508-CFTR Functional
Expression Defect
#MMPMID27168400
Veit G
; Oliver K
; Apaja PM
; Perdomo D
; Bidaud-Meynard A
; Lin ST
; Guo J
; Icyuz M
; Sorscher EJ
; Hartman JL IV
; Lukacs GL
PLoS Biol
2016[May]; 14
(5
): e1002462
PMID27168400
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The most common cystic fibrosis (CF) causing mutation, deletion of phenylalanine
508 (?F508 or Phe508del), results in functional expression defect of the CF
transmembrane conductance regulator (CFTR) at the apical plasma membrane (PM) of
secretory epithelia, which is attributed to the degradation of the misfolded
channel at the endoplasmic reticulum (ER). Deletion of phenylalanine 670 (?F670)
in the yeast oligomycin resistance 1 gene (YOR1, an ABC transporter) of
Saccharomyces cerevisiae phenocopies the ?F508-CFTR folding and trafficking
defects. Genome-wide phenotypic (phenomic) analysis of the Yor1-?F670 biogenesis
identified several modifier genes of mRNA processing and translation, which
conferred oligomycin resistance to yeast. Silencing of orthologues of these
candidate genes enhanced the ?F508-CFTR functional expression at the apical PM in
human CF bronchial epithelia. Although knockdown of RPL12, a component of the
ribosomal stalk, attenuated the translational elongation rate, it increased the
folding efficiency as well as the conformational stability of the ?F508-CFTR,
manifesting in 3-fold augmented PM density and function of the mutant.
Combination of RPL12 knockdown with the corrector drug, VX-809 (lumacaftor)
restored the mutant function to ~50% of the wild-type channel in primary
CFTR?F508/?F508 human bronchial epithelia. These results and the observation that
silencing of other ribosomal stalk proteins partially rescue the loss-of-function
phenotype of ?F508-CFTR suggest that the ribosomal stalk modulates the folding
efficiency of the mutant and is a potential therapeutic target for correction of
the ?F508-CFTR folding defect.
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