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Open AccessArticle

Phosphorylation of the Chaperone-Like HspB5 Rescues Trafficking and Function of F508del-CFTR

1
Univ Paris Est Creteil, INSERM, IMRB, F-94010 Creteil, France
2
AP-HP, Hôpital Henri Mondor, Département de Génétique, F-94010 Creteil, France
3
Centre Hospitalier Intercommunal de Creteil, Service d’ORL et de Chirurgie Cervico-Faciale, F-94010 Creteil, France
4
The Hospital for Sick Children and the University of Toronto, Toronto, ON M5G 0A4, Canada
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(14), 4844; https://doi.org/10.3390/ijms21144844
Received: 18 June 2020 / Revised: 2 July 2020 / Accepted: 4 July 2020 / Published: 8 July 2020
(This article belongs to the Special Issue Therapeutic Approaches for Cystic Fibrosis)
Cystic Fibrosis is a lethal monogenic autosomal recessive disease linked to mutations in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein. The most frequent mutation is the deletion of phenylalanine at position 508 of the protein. This F508del-CFTR mutation leads to misfolded protein that is detected by the quality control machinery within the endoplasmic reticulum and targeted for destruction by the proteasome. Modulating quality control proteins as molecular chaperones is a promising strategy for attenuating the degradation and stabilizing the mutant CFTR at the plasma membrane. Among the molecular chaperones, the small heat shock protein HspB1 and HspB4 were shown to promote degradation of F508del-CFTR. Here, we investigated the impact of HspB5 expression and phosphorylation on transport to the plasma membrane, function and stability of F508del-CFTR. We show that a phosphomimetic form of HspB5 increases the transport to the plasma membrane, function and stability of F508del-CFTR. These activities are further enhanced in presence of therapeutic drugs currently used for the treatment of cystic fibrosis (VX-770/Ivacaftor, VX-770+VX-809/Orkambi). Overall, this study highlights the beneficial effects of a phosphorylated form of HspB5 on F508del-CFTR rescue and its therapeutic potential in cystic fibrosis. View Full-Text
Keywords: cystic fibrosis; CFTR; HspB5; alpha B-crystallin; CRYAB; phosphorylation cystic fibrosis; CFTR; HspB5; alpha B-crystallin; CRYAB; phosphorylation
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Degrugillier, F.; Aissat, A.; Prulière-Escabasse, V.; Bizard, L.; Simonneau, B.; Decrouy, X.; Jiang, C.; Rotin, D.; Fanen, P.; Simon, S. Phosphorylation of the Chaperone-Like HspB5 Rescues Trafficking and Function of F508del-CFTR. Int. J. Mol. Sci. 2020, 21, 4844.

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