4.7 Article

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

期刊

BIOMEDICINES
卷 9, 期 9, 页码 -

出版社

MDPI
DOI: 10.3390/biomedicines9091121

关键词

Spns2; S1P; sphingosine; SphK1; SGPL1; cystic fibrosis; sphingolipid; lung

资金

  1. University of Milan, Italy, Piano di Sostegno alla Ricerca 2018, finanziamento LINEA 2 Dotazione annuale per attivita istituzionale
  2. Italian Cystic Fibrosis Research Foundation (Grant FFC) [11-2016]
  3. University of Milan

向作者/读者索取更多资源

The role of S1P in Cystic Fibrosis has been studied since 2001, with research showing that CFTR mutation in CF patients is associated with altered S1P expression. CF patients show increased S1P accumulation due to up-regulation of SphK1 and down-regulation of SGPL1, along with deficient expression of Spns2 transporter. This excessive accumulation is partially prevented by up-regulated phosphatases in CF 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 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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