Cystic Fibrosis: A Literature Review

On researching new developments in the treatment of cystic fibrosis, I came across a very interesting article: “Ribosomal Stalk Protein Silencing Partially Corrects the ΔF508-CFTR Functional Expression Defect.” In the article, Viet et al1 reveal the potential application of the silencing of RPL12 (Ribosomal Protein L12), to correct the ΔF508-CFTR biogenesis defect. As you know, cystic fibrosis is caused by a defect in the CF transmembrane conductance regulator (CFTR gene), or more specifically, mutations in the CTFR gene, the most prominent of which is the deletion of three nucleotides at position 508 of the CFTR gene on chromosome 7. Having the knowledge that the aforementioned deletion results in an abnormal CFTR protein that lacks phenylalanine
residue and thus has channel misfolding which in turn causes degradation within the cell, as well as drawing from a recent study by Meriin et al. titled, “A Novel Approach to Recovery of Function of Mutant Proteins by Slowing Down Translation,” where a new approach to treatment of protein-misfolding disorders through a mutant CFTR function is introduced, Viet et al hypothesized that reduced translation elongation increases ΔF508-CFTR folding. Thus, the group intended to test the effects of translational elongation rate on the expression of functional ΔF508-CFTR, as well as various other things such as RPL12.
When they conducted the study, the slowing down of translational elongation rate actually partially reverted the folding and processing defects of ΔF508-CFTR. But the tests did not stop there. Other experiments conducted for study include silencing human homologs of yeast Yor-1-ΔF670 biogenesis modifier genes by using the human CF bronchial epithelial CFBE cell line with CFTRΔF508/ΔF508 genetic background, SiRNA-mediated knockdown of RPL12, RPL12 knockdown, RPL12 silencing, and SiRNA-mediated silencing of ribosomal stalk proteins, among other things. RPL12 knockdown confirmed the relevance of RPL12 silencing on correcting misprocessing of ΔF508-CFTR and increased the ΔF508-CFTR efficiency at the Endoplasmic Reticulum. RPL12 silencing in combination with VX-809, a corrector drug, increased the functional expression of ΔF508-CFTR in “immortalized and primary human bronchial epithelia.” And last but not least, SiRNA-mediated silencing of ribosomal stalk proteins resulted in an increase in the functional expression of ΔF508-CFTR, as well as its
stability.
In sum, the study comes to the conclusion that silencing of the ribosomal stalk protein increased the folding and stabilization of ΔF508-CFTR, resulting in its increased plasma membrane expression and function. It is amazing to think that a cure for cystic fibrosis might not be far off. And through this study we have yet another example of the importance of ribosomes in gene expression, with this new revelation having many implications that could extend beyond cystic fibrosis and unto other diseases and conditions.