The Autophagy Inhibitor Spautin-1 Antagonizes Rescue of Mutant CFTR Through an Autophagy-Independent and USP13-Mediated Mechanism

Emanuela Pesce, Elvira Sondo, Loretta Ferrera, Valeria Tomati, Emanuela Caci, Paolo Scudieri, Ilaria Musante, Mario Renda, Nesrine Baatallah, Nathalie Servel, Alexandre Hinzpeter, Diego di Bernardo, Nicoletta Pedemonte, Luis J V Galietta

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)1464
JournalFrontiers in Pharmacology
Volume9
DOIs
Publication statusPublished - 2018

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    Pesce, E., Sondo, E., Ferrera, L., Tomati, V., Caci, E., Scudieri, P., Musante, I., Renda, M., Baatallah, N., Servel, N., Hinzpeter, A., di Bernardo, D., Pedemonte, N., & Galietta, L. J. V. (2018). The Autophagy Inhibitor Spautin-1 Antagonizes Rescue of Mutant CFTR Through an Autophagy-Independent and USP13-Mediated Mechanism. Frontiers in Pharmacology, 9, 1464. https://doi.org/10.3389/fphar.2018.01464