Combination of Correctors Rescue ΔF508-CFTR by Reducing Its Association with Hsp40 and Hsp27.

The Journal of Biological Chemistry
Miquéias Lopes-PachecoLiudmila Cebotaru

Abstract

Correcting the processing of ΔF508-CFTR, the most common mutation in cystic fibrosis, is the major goal in the development of new therapies for this disease. Here, we determined whether ΔF508 could be rescued by a combination of small-molecule correctors, and identified the mechanism by which correctors rescue the trafficking mutant of cystic fibrosis transmembrane conductance regulator (CFTR). We transfected COS-7 cells with ΔF508, created HEK-293 stably expressing ΔF508, and utilized CFBE41o(-) cell lines stably transduced with ΔF508. As shown previously, ΔF508 expressed less protein, was unstable at physiological temperature, and rapidly degraded. When the cells were treated with the combination C18 + C4 the mature C-band was expressed at the cell surface. After treatment with C18 + C4, we saw a lower rate of protein disappearance after translation was stopped with cycloheximide. To understand how this rescue occurs, we evaluated the change in the binding of proteins involved in endoplasmic reticulum-associated degradation, such as Hsp27 (HspB1) and Hsp40 (DnaJ). We saw a dramatic reduction in binding to heat shock proteins 27 and 40 following combined corrector therapy. siRNA experiments confirmed that a reduction in Hsp27 ...Continue Reading

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Citations

Sep 23, 2016·Frontiers in Pharmacology·Miquéias Lopes-Pacheco
Feb 7, 2018·Frontiers in Pharmacology·Sang Hyun LimIgor Stagljar
Jun 8, 2018·The Journal of Biological Chemistry·Murali K YandaLiudmila Cebotaru
Feb 13, 2016·Chembiochem : a European Journal of Chemical Biology·Miquéias Lopes-PachecoLiudmila Cebotaru
Aug 31, 2020·Human Gene Therapy·William B GugginoLiudmila Cebotaru
Mar 11, 2020·Frontiers in Pharmacology·Miquéias Lopes-Pacheco
Nov 12, 2019·American Journal of Physiology. Gastrointestinal and Liver Physiology·Murali K YandaLiudmila Cebotaru
Jul 12, 2020·International Journal of Molecular Sciences·Fanny DegrugillierStéphanie Simon
Oct 10, 2018·Nature Medicine·Guido VeitGergely L Lukacs
Mar 3, 2021·Liver International : Official Journal of the International Association for the Study of the Liver·Amel Ben SaadThomas Falguières
Sep 24, 2018·Experimental Cell Research·Miquéias Lopes-PachecoPatricia R M Rocco
May 1, 2021·International Journal of Molecular Sciences·Stéphanie SimonAndré-Patrick Arrigo
May 4, 2021·Frontiers in Pharmacology·Lisa KünziStefanie Krick
Jul 31, 2021·Journal of Experimental Pharmacology·Madalena C PintoMiquéias Lopes-Pacheco
Jul 31, 2021·Cellular and Molecular Gastroenterology and Hepatology·Murali K YandaLiudmila Cebotaru

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