Pharmacological chaperone-rescued cystic fibrosis CFTR-F508del mutant overcomes PRAF2-gated access to endoplasmic reticulum exit sites.
Kusumika SahaBenoit ChevalierStéphane DolyNesrine BaatallahThomas GuilbertIwona PrankeMark G H ScottHervé EnslenChiara GuerreraCérina ChuonAleksander EdelmanIsabelle Sermet-GaudelusAlexandre HinzpeterStefano MarulloPublished in: Cellular and molecular life sciences : CMLS (2022)
The endoplasmic reticulum exit of some polytopic plasma membrane proteins (PMPs) is controlled by arginin-based retention motifs. PRAF2, a gatekeeper which recognizes these motifs, was shown to retain the GABA B -receptor GB1 subunit in the ER. We report that PRAF2 can interact on a stoichiometric basis with both wild type and mutant F508del Cystic Fibrosis (CF) Transmembrane Conductance Regulator (CFTR), preventing the access of newly synthesized cargo to ER exit sites. Because of its lower abundance, compared to wild-type CFTR, CFTR-F508del recruitment into COPII vesicles is suppressed by the ER-resident PRAF2. We also demonstrate that some pharmacological chaperones that efficiently rescue CFTR-F508del loss of function in CF patients target CFTR-F508del retention by PRAF2 operating with various mechanisms. Our findings open new therapeutic perspectives for diseases caused by the impaired cell surface trafficking of mutant PMPs, which contain RXR-based retention motifs that might be recognized by PRAF2.
Keyphrases
- cystic fibrosis
- endoplasmic reticulum
- wild type
- pseudomonas aeruginosa
- lung function
- end stage renal disease
- cell surface
- chronic kidney disease
- ejection fraction
- transcription factor
- minimally invasive
- patient safety
- peritoneal dialysis
- patient reported outcomes
- quality improvement
- oxidative stress
- heat shock
- binding protein
- air pollution
- chronic obstructive pulmonary disease
- patient reported