%0 Generic %A Pesce, Emanuela %A Sondo, Elvira %A Ferrera, Loretta %A Tomati, Valeria %A Caci, Emanuela %A Scudieri, Paolo %A Musante, Ilaria %A Renda, Mario %A Baatallah, Nesrine %A Servel, Nathalie %A Hinzpeter, Alexandre %A Bernardo, Diego di %A Pedemonte, Nicoletta %A J. V. Galietta, Luis %D 2018 %T Data_Sheet_1_The Autophagy Inhibitor Spautin-1 Antagonizes Rescue of Mutant CFTR Through an Autophagy-Independent and USP13-Mediated Mechanism.pdf %U https://frontiersin.figshare.com/articles/dataset/Data_Sheet_1_The_Autophagy_Inhibitor_Spautin-1_Antagonizes_Rescue_of_Mutant_CFTR_Through_an_Autophagy-Independent_and_USP13-Mediated_Mechanism_pdf/7459652 %R 10.3389/fphar.2018.01464.s001 %2 https://frontiersin.figshare.com/ndownloader/files/13812722 %K CFTR %K chloride channel %K cystic fibrosis %K autophagy %K ubiquitination %K spautin-1 %X

The mutation F508del, responsible for a majority of cystic fibrosis cases, provokes the instability and misfolding of the CFTR chloride channel. Pharmacological recovery of F508del-CFTR may be obtained with small molecules called correctors. However, treatment with a single corrector in vivo and in vitro only leads to a partial rescue, a consequence of cell quality control systems that still detect F508del-CFTR as a defective protein causing its degradation. We tested the effect of spautin-1 on F508del-CFTR since it is an inhibitor of USP10 deubiquitinase and of autophagy, a target and a biological process that have been associated with cystic fibrosis and mutant CFTR. We found that short-term treatment of cells with spautin-1 downregulates the function and expression of F508del-CFTR despite the presence of corrector VX-809, a finding obtained in multiple cell models and assays. In contrast, spautin-1 was ineffective on wild type CFTR. Silencing and upregulation of USP13 (another target of spautin-1) but not of USP10, had opposite effects on F508del-CFTR expression/function. In contrast, modulation of autophagy with known activators or inhibitors did not affect F508del-CFTR. Our results identify spautin-1 as a novel chemical probe to investigate the molecular mechanisms that prevent full rescue of mutant CFTR.

%I Frontiers