Pesce, Emanuela Sondo, Elvira Ferrera, Loretta Tomati, Valeria Caci, Emanuela Scudieri, Paolo Musante, Ilaria Renda, Mario Baatallah, Nesrine Servel, Nathalie Hinzpeter, Alexandre Bernardo, Diego di Pedemonte, Nicoletta J. V. Galietta, Luis Data_Sheet_1_The Autophagy Inhibitor Spautin-1 Antagonizes Rescue of Mutant CFTR Through an Autophagy-Independent and USP13-Mediated Mechanism.pdf <p>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.</p> CFTR;chloride channel;cystic fibrosis;autophagy;ubiquitination;spautin-1 2018-12-13
    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
10.3389/fphar.2018.01464.s001