Abstract
Aberrant ceramide build-up in preeclampsia, a serious disorder of pregnancy, causes exuberant autophagy-mediated trophoblast cell death. The significance of ceramide accumulation for lysosomal biogenesis in preeclampsia is unknown. Here we report that lysosome formation is markedly increased in trophoblast cells of early-onset preeclamptic placentae, in particular in syncytiotrophoblasts. This is accompanied by augmented levels of transcription factor EB (TFEB). In vitro and in vivo experiments demonstrate that ceramide increases TFEB expression and nuclear translocation and induces lysosomal formation and exocytosis. Further, we show that TFEB directly regulates the expression of lysosomal sphingomyelin phosphodiesterase (L-SMPD1) that degrades sphingomyelin to ceramide. In early-onset preeclampsia, ceramide-induced lysosomal exocytosis carries L-SMPD1 to the apical membrane of the syncytial epithelium, resulting in ceramide accumulation in lipid rafts and release of active L-SMPD1 via ceramide-enriched exosomes into the maternal circulation. The SMPD1-containing exosomes promote endothelial activation and impair endothelial tubule formation in vitro. Both exosome-induced processes are attenuated by SMPD1 inhibitors. These findings suggest that ceramide-induced lysosomal biogenesis and exocytosis in preeclamptic placentae contributes to maternal endothelial dysfunction, characteristic of this pathology.
Highlights
Lysosomes are acidic organelles that degrade and recycle unwanted material and damaged intracellular components, including membranes, lipids and proteins (Mizushima et al, 2008; Luzio et al, 2009)
Dephosphorylated Transcription Factor EB (TFEB) translocates to the nucleus, where it binds to the palindromic motif (TCACGTGA) of coordinated lysosomal expression and regulation (CLEAR) elements thereby inducing the transcription of an array of genes involved in lysosomal biogenesis and autophagy (Settembre et al, 2013; Martina and Puertollano, 2017)
We demonstrate exuberant lysosomal biogenesis in the syncytium of early-onset preeclamptic placentae that is due to the elevated ceramide build-up in this layer (MellandSmith et al, 2015)
Summary
Lysosomes are acidic organelles that degrade and recycle unwanted material and damaged intracellular components, including membranes, lipids and proteins (Mizushima et al, 2008; Luzio et al, 2009). Lysosomes are subjected to lysosomal exocytosis (Medina et al, 2011) In the latter process, lysosomes are targeted to the plasma membrane where they fuse and release their contents. Lysosome Biogenesis in Preeclampsia outside the cells (Chieregatti and Meldolesi, 2005), thereby contributing to plasma membrane repair, cell signaling and immune responses (Rodriguez et al, 1997; Andrews, 2000; Bossi and Griffiths, 2005). A gene network termed coordinated lysosomal expression and regulation (CLEAR) regulates lysosomal biogenesis and function (Sardiello et al, 2009). Dephosphorylated TFEB translocates to the nucleus, where it binds to the palindromic motif (TCACGTGA) of CLEAR elements thereby inducing the transcription of an array of genes involved in lysosomal biogenesis and autophagy (Settembre et al, 2013; Martina and Puertollano, 2017). TFEB’s modulation of transcriptional networks is cell-type and context dependent
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