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Spns2 Transporter Contributes to the Accumulation of S1P in Cystic Fibrosis Human Bronchial Epithelial Cells

The role of S1P in Cystic Fibrosis (CF) has been investigated since 2001, when it was first described that the CFTR channel regulates the inward transport of S1P. From then on, various studies have associated F508del CFTR, the most frequent mutation in CF patients, with altered S1P expression in tis...

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Autores principales: Zulueta, Aida, Dei Cas, Michele, Luciano, Francesco, Mingione, Alessandra, Pivari, Francesca, Righi, Ilaria, Morlacchi, Letizia, Rosso, Lorenzo, Signorelli, Paola, Ghidoni, Riccardo, Paroni, Rita, Caretti, Anna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8467635/
https://www.ncbi.nlm.nih.gov/pubmed/34572307
http://dx.doi.org/10.3390/biomedicines9091121
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author Zulueta, Aida
Dei Cas, Michele
Luciano, Francesco
Mingione, Alessandra
Pivari, Francesca
Righi, Ilaria
Morlacchi, Letizia
Rosso, Lorenzo
Signorelli, Paola
Ghidoni, Riccardo
Paroni, Rita
Caretti, Anna
author_facet Zulueta, Aida
Dei Cas, Michele
Luciano, Francesco
Mingione, Alessandra
Pivari, Francesca
Righi, Ilaria
Morlacchi, Letizia
Rosso, Lorenzo
Signorelli, Paola
Ghidoni, Riccardo
Paroni, Rita
Caretti, Anna
author_sort Zulueta, Aida
collection PubMed
description The role of S1P in Cystic Fibrosis (CF) has been investigated since 2001, when it was first described that the CFTR channel regulates the inward transport of S1P. From then on, various studies have associated F508del CFTR, the most frequent mutation in CF patients, with altered S1P expression in tissue and plasma. We found that human bronchial epithelial immortalized and primary cells from CF patients express more S1P than the control cells, as evidenced by mass spectrometry analysis. S1P accumulation relies on two- to four-fold transcriptional up-regulation of SphK1 and simultaneous halving of SGPL1 in CF vs. control cells. The reduction of SGPL1 transcription protects S1P from irreversible degradation, but the excessive accumulation is partially prevented by the action of the two phosphatases that are up-regulated compared to control cells. For the first time in CF, we describe that Spns2, a non-ATP dependent transporter that normally extrudes S1P out of the cells, shows deficient transcriptional and protein expression, thus impairing S1P accrual dissipation. The in vitro data on CF human bronchial epithelia correlates with the impaired expression of Spns2 observed in CF human lung biopsies compared to healthy control.
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spelling pubmed-84676352021-09-27 Spns2 Transporter Contributes to the Accumulation of S1P in Cystic Fibrosis Human Bronchial Epithelial Cells Zulueta, Aida Dei Cas, Michele Luciano, Francesco Mingione, Alessandra Pivari, Francesca Righi, Ilaria Morlacchi, Letizia Rosso, Lorenzo Signorelli, Paola Ghidoni, Riccardo Paroni, Rita Caretti, Anna Biomedicines Article The role of S1P in Cystic Fibrosis (CF) has been investigated since 2001, when it was first described that the CFTR channel regulates the inward transport of S1P. From then on, various studies have associated F508del CFTR, the most frequent mutation in CF patients, with altered S1P expression in tissue and plasma. We found that human bronchial epithelial immortalized and primary cells from CF patients express more S1P than the control cells, as evidenced by mass spectrometry analysis. S1P accumulation relies on two- to four-fold transcriptional up-regulation of SphK1 and simultaneous halving of SGPL1 in CF vs. control cells. The reduction of SGPL1 transcription protects S1P from irreversible degradation, but the excessive accumulation is partially prevented by the action of the two phosphatases that are up-regulated compared to control cells. For the first time in CF, we describe that Spns2, a non-ATP dependent transporter that normally extrudes S1P out of the cells, shows deficient transcriptional and protein expression, thus impairing S1P accrual dissipation. The in vitro data on CF human bronchial epithelia correlates with the impaired expression of Spns2 observed in CF human lung biopsies compared to healthy control. MDPI 2021-08-31 /pmc/articles/PMC8467635/ /pubmed/34572307 http://dx.doi.org/10.3390/biomedicines9091121 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Zulueta, Aida
Dei Cas, Michele
Luciano, Francesco
Mingione, Alessandra
Pivari, Francesca
Righi, Ilaria
Morlacchi, Letizia
Rosso, Lorenzo
Signorelli, Paola
Ghidoni, Riccardo
Paroni, Rita
Caretti, Anna
Spns2 Transporter Contributes to the Accumulation of S1P in Cystic Fibrosis Human Bronchial Epithelial Cells
title Spns2 Transporter Contributes to the Accumulation of S1P in Cystic Fibrosis Human Bronchial Epithelial Cells
title_full Spns2 Transporter Contributes to the Accumulation of S1P in Cystic Fibrosis Human Bronchial Epithelial Cells
title_fullStr Spns2 Transporter Contributes to the Accumulation of S1P in Cystic Fibrosis Human Bronchial Epithelial Cells
title_full_unstemmed Spns2 Transporter Contributes to the Accumulation of S1P in Cystic Fibrosis Human Bronchial Epithelial Cells
title_short Spns2 Transporter Contributes to the Accumulation of S1P in Cystic Fibrosis Human Bronchial Epithelial Cells
title_sort spns2 transporter contributes to the accumulation of s1p in cystic fibrosis human bronchial epithelial cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8467635/
https://www.ncbi.nlm.nih.gov/pubmed/34572307
http://dx.doi.org/10.3390/biomedicines9091121
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