Ceramide phosphoethanolamine synthase SMSr is a target of caspase-6 during apoptotic cell death
Autor(en): | Cabukusta, Birol Nettebrock, Niclas T. Kol, Matthijs Hilderink, Angelika Tafesse, Fikadu G. Holthuis, Joost C. M. |
Stichwörter: | ACTIVATION; ALPHA; Biochemistry & Molecular Biology; Cell Biology; CLEAVAGE; DISTINCT; ENDOPLASMIC-RETICULUM; NF-KAPPA-B; PROTEIN SMSR; RADIATION-INDUCED APOPTOSIS; SPHINGOLIPID BIOSYNTHESIS; SPHINGOMYELIN SYNTHASE-1 | Erscheinungsdatum: | 2017 | Herausgeber: | PORTLAND PRESS LTD | Journal: | BIOSCIENCE REPORTS | Volumen: | 37 | Ausgabe: | 4 | Zusammenfassung: | 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 alpha-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. |
ISSN: | 01448463 | DOI: | 10.1042/BSR20170867 |
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