Sphingomyelin synthase-related protein SMSr is a suppressor of ceramide-induced mitochondrial apoptosis

Fikadu G. Tafesse, Ana M. Vacaru, Elleke F. Bosma, Martin Hermansson, Amrita Jain, Angelika Hilderink, Pentti Somerharju, Joost C.M. Holthuis

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

Cells synthesize ceramides in the endoplasmic reticulum (ER) as precursors for sphingolipids to form an impermeable plasma membrane. As ceramides are engaged in apoptotic pathways, cells would need to monitor their levels closely to avoid killing themselves during sphingolipid biosynthesis. How this is accomplished remains to be established. Here we identify SMSr (SAMD8), an ER-resident ceramide phosphoethanolamine (CPE) synthase, as a suppressor of ceramide-mediated cell death. Disruption of SMSr catalytic activity causes a rise in ER ceramides and their mislocalization to mitochondria, triggering a mitochondrial pathway of apoptosis. Blocking de novo ceramide synthesis, stimulating ceramide export from the ER or targeting a bacterial ceramidase to mitochondria rescues SMSr-deficient cells from apoptosis. We also show that SMSr-catalyzed CPE production, although essential, is not sufficient to suppress ceramide-induced cell death and that SMSr-mediated ceramide homeostasis requires the N-terminal sterile a-motif, or SAM domain, of the enzyme. These results define ER ceramides as bona fide transducers of mitochondrial apoptosis and indicate a primary role of SMSr in monitoring ER ceramide levels to prevent inappropriate cell death during sphingolipid biosynthesis.

Original languageEnglish (US)
Pages (from-to)445-454
Number of pages10
JournalJournal of Cell Science
Volume127
Issue number2
DOIs
StatePublished - Jan 2014

Keywords

  • Ceramide homeostasis
  • Ceramide phosphoethanolamine
  • Mitochondrial apoptosis
  • SAM domain
  • Sphingomyelin synthase-related protein

ASJC Scopus subject areas

  • Cell Biology

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  • Cite this

    Tafesse, F. G., Vacaru, A. M., Bosma, E. F., Hermansson, M., Jain, A., Hilderink, A., Somerharju, P., & Holthuis, J. C. M. (2014). Sphingomyelin synthase-related protein SMSr is a suppressor of ceramide-induced mitochondrial apoptosis. Journal of Cell Science, 127(2), 445-454. https://doi.org/10.1242/jcs.138933