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. 2022 Sep 27;79(10):530.
doi: 10.1007/s00018-022-04554-1.

Pharmacological chaperone-rescued cystic fibrosis CFTR-F508del mutant overcomes PRAF2-gated access to endoplasmic reticulum exit sites

Kusumika Saha  1   2 , Benoit Chevalier  3 , Stéphane Doly  1   4 , Nesrine Baatallah  3 , Thomas Guilbert  1 , Iwona Pranke  3 , Mark G H Scott  1 , Hervé Enslen  1 , Chiara Guerrera  5 , Cérina Chuon  5 , Aleksander Edelman  3 , Isabelle Sermet-Gaudelus  3   6 , Alexandre Hinzpeter #  3 , Stefano Marullo #  7
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Pharmacological chaperone-rescued cystic fibrosis CFTR-F508del mutant overcomes PRAF2-gated access to endoplasmic reticulum exit sites

Kusumika Saha et al. Cell Mol Life Sci. .

Abstract

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 GABAB-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.

Keywords: Arginin-based retention motif; BRET; CFTR; Corrector; ERES; Gatekeeper; Protein export; Sec 24; Sec 31.

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