Spns2 Transporter Contributes to the Accumulation of S1P in Cystic Fibrosis Human Bronchial Epithelial Cells
Aida Zulueta,
Michele Dei Cas,
Francesco Luciano,
Alessandra Mingione,
Francesca Pivari,
Ilaria Righi,
Letizia Morlacchi,
Lorenzo Rosso,
Paola Signorelli,
Riccardo Ghidoni,
Rita Paroni,
Anna Caretti
Affiliations
Aida Zulueta
Biochemistry and Molecular Biology Laboratory, Department of Health Sciences, University of Milan, 20142 Milan, Italy
Michele Dei Cas
Clinical Biochemistry and Mass Spectrometry Laboratory, Department of Health Sciences, University of Milan, 20142 Milan, Italy
Francesco Luciano
Biochemistry and Molecular Biology Laboratory, Department of Health Sciences, University of Milan, 20142 Milan, Italy
Alessandra Mingione
Biochemistry and Molecular Biology Laboratory, Department of Health Sciences, University of Milan, 20142 Milan, Italy
Francesca Pivari
Biochemistry and Molecular Biology Laboratory, Department of Health Sciences, University of Milan, 20142 Milan, Italy
Ilaria Righi
Thoracic Surgery and Lung Transplant Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
Letizia Morlacchi
Respiratory Unit and Cystic Fibrosis Center, Internal Medicine Department, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
Lorenzo Rosso
Thoracic Surgery and Lung Transplant Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
Paola Signorelli
Biochemistry and Molecular Biology Laboratory, Department of Health Sciences, University of Milan, 20142 Milan, Italy
Riccardo Ghidoni
Biochemistry and Molecular Biology Laboratory, Department of Health Sciences, University of Milan, 20142 Milan, Italy
Rita Paroni
Clinical Biochemistry and Mass Spectrometry Laboratory, Department of Health Sciences, University of Milan, 20142 Milan, Italy
Anna Caretti
Biochemistry and Molecular Biology Laboratory, Department of Health Sciences, University of Milan, 20142 Milan, Italy
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.
