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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Autophagy
Cystic Fibrosis
Biological Phenomena
Chloride Channels
Quality Control
Up-Regulation
Down-Regulation
spautin-1
Pharmacology
Mutation
Proteins

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The Autophagy Inhibitor Spautin-1 Antagonizes Rescue of Mutant CFTR Through an Autophagy-Independent and USP13-Mediated Mechanism. / Pesce, Emanuela; Sondo, Elvira; Ferrera, Loretta; Tomati, Valeria; Caci, Emanuela; Scudieri, Paolo; Musante, Ilaria; Renda, Mario; Baatallah, Nesrine; Servel, Nathalie; Hinzpeter, Alexandre; di Bernardo, Diego; Pedemonte, Nicoletta; Galietta, Luis J V.

In: Frontiers in Pharmacology, Vol. 9, 2018, p. 1464.

Research output: Contribution to journalArticle

Pesce, Emanuela ; Sondo, Elvira ; Ferrera, Loretta ; Tomati, Valeria ; Caci, Emanuela ; Scudieri, Paolo ; Musante, Ilaria ; Renda, Mario ; Baatallah, Nesrine ; Servel, Nathalie ; Hinzpeter, Alexandre ; di Bernardo, Diego ; Pedemonte, Nicoletta ; Galietta, Luis J V. / The Autophagy Inhibitor Spautin-1 Antagonizes Rescue of Mutant CFTR Through an Autophagy-Independent and USP13-Mediated Mechanism. In: Frontiers in Pharmacology. 2018 ; Vol. 9. pp. 1464.
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AU - Tomati, Valeria

AU - Caci, Emanuela

AU - Scudieri, Paolo

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AU - Renda, Mario

AU - Baatallah, Nesrine

AU - Servel, Nathalie

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N2 - 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.

AB - 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.

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