Ceramide phosphoethanolamine synthase SMSr is a target of caspase-6 during apoptotic cell death

Birol Cabukusta, Niclas T. Nettebrock, Matthijs Kol, Angelika Hilderink, Fikadu Tafesse, Joost C.M. Holthuis

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2 Scopus citations

Abstract

Ceramides are essential precursors of sphingolipids with a dual role as mediators of apoptotic cell death. Previous work revealed that the ER-resident ceramide phosphoethanolamine (CPE) synthase SMSr/SAMD8 is a suppressor of ceramide-mediated apoptosis in cultured cells. Anti-apoptotic activity of SMSr requires a catalytically active enzyme but also relies on the enzyme’s N-terminal sterile a-motif or SAM domain. Here, we demonstrate that SMSr itself is a target of the apoptotic machinery. Treatment of cells with staurosporine or the death receptor ligand FasL triggers caspase-mediated cleavage of SMSr at a conserved aspartate located downstream of the enzyme’s SAM domain and upstream of its first membrane span. Taking advantage of reconstitution experiments with SMSr produced in a cell-free expression system, specific caspase-inhibitors and gene silencing approaches, we show that SMSr is a novel and specific substrate of caspase-6, a non-conventional effector caspase implicated in Huntington’s and Alzheimer’s diseases. Our findings underscore a role of SMSr as negative regulator of ceramide-induced cell death and, in view of a prominent expression of the enzyme in brain, raise questions regarding its potential involvement in neurodegenerative disorders.

Original languageEnglish (US)
Article numberBSR20170867
JournalBioscience Reports
Volume37
Issue number4
DOIs
Publication statusPublished - Aug 31 2017

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ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Cabukusta, B., Nettebrock, N. T., Kol, M., Hilderink, A., Tafesse, F., & Holthuis, J. C. M. (2017). Ceramide phosphoethanolamine synthase SMSr is a target of caspase-6 during apoptotic cell death. Bioscience Reports, 37(4), [BSR20170867]. https://doi.org/10.1042/BSR20170867