title: Sphingomyelin synthase-related protein SMSr is a suppressor of ceramide-induced mitochondrial apoptosis.
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 α-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.
authors.affiliation: Membrane Enzymology, Bijvoet Center and Institute of Biomembranes, Utrecht University, 3584 CH Utrecht, the Netherlands.
authors.forename: Fikadu G
authors.initials: FG
authors.lastname: Tafesse
authors.forename: Ana M
authors.initials: AM
authors.lastname: Vacaru
authors.forename: Elleke F
authors.initials: EF
authors.lastname: Bosma
authors.forename: Martin
authors.initials: M
authors.lastname: Hermansson
authors.forename: Amrita
authors.initials: A
authors.lastname: Jain
authors.forename: Angelika
authors.initials: A
authors.lastname: Hilderink
authors.forename: Pentti
authors.initials: P
authors.lastname: Somerharju
authors.forename: Joost C M
authors.initials: JC
authors.lastname: Holthuis
mesh_terms: D017209:Apoptosis; D055162:Biocatalysis; D055572:Ceramidases / Q000378:metabolism; D002518:Ceramides / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D018390:Gene Targeting; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D013109:Sphingomyelins / Q000378:metabolism; D017855:Transferases (Other Substituted Phosphate Groups) / Q000378:metabolism*
chemical_list: D002518:Ceramides; D034741:RNA, Small Interfering; D013109:Sphingomyelins; C060281:ceramide phosphoethanolamine; C000592293:SAMD8 protein, human; D017855:Transferases (Other Substituted Phosphate Groups); C070186:phosphatidylcholine-ceramide phosphocholine transferase; D055572:Ceramidases
keywords: Ceramide homeostasis; Ceramide phosphoethanolamine; Mitochondrial apoptosis; SAM domain; Sphingomyelin synthase-related protein