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Ceramide phosphoethanolamine synthase SMSr is a target of caspase-6 during apoptotic cell death
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 S...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Portland Press Ltd.
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567093/ https://www.ncbi.nlm.nih.gov/pubmed/28659495 http://dx.doi.org/10.1042/BSR20170867 |
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author | Cabukusta, Birol Nettebrock, Niclas T. Kol, Matthijs Hilderink, Angelika Tafesse, Fikadu G. Holthuis, Joost C.M. |
author_facet | Cabukusta, Birol Nettebrock, Niclas T. Kol, Matthijs Hilderink, Angelika Tafesse, Fikadu G. Holthuis, Joost C.M. |
author_sort | Cabukusta, Birol |
collection | PubMed |
description | 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 α-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. |
format | Online Article Text |
id | pubmed-5567093 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Portland Press Ltd. |
record_format | MEDLINE/PubMed |
spelling | pubmed-55670932017-09-01 Ceramide phosphoethanolamine synthase SMSr is a target of caspase-6 during apoptotic cell death Cabukusta, Birol Nettebrock, Niclas T. Kol, Matthijs Hilderink, Angelika Tafesse, Fikadu G. Holthuis, Joost C.M. Biosci Rep Research Articles 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 α-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. Portland Press Ltd. 2017-07-17 /pmc/articles/PMC5567093/ /pubmed/28659495 http://dx.doi.org/10.1042/BSR20170867 Text en © 2017 The Author(s). http://creativecommons.org/licenses/by/4.0/This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY) (http://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Articles Cabukusta, Birol Nettebrock, Niclas T. Kol, Matthijs Hilderink, Angelika Tafesse, Fikadu G. Holthuis, Joost C.M. Ceramide phosphoethanolamine synthase SMSr is a target of caspase-6 during apoptotic cell death |
title | Ceramide phosphoethanolamine synthase SMSr is a target of caspase-6 during apoptotic cell death |
title_full | Ceramide phosphoethanolamine synthase SMSr is a target of caspase-6 during apoptotic cell death |
title_fullStr | Ceramide phosphoethanolamine synthase SMSr is a target of caspase-6 during apoptotic cell death |
title_full_unstemmed | Ceramide phosphoethanolamine synthase SMSr is a target of caspase-6 during apoptotic cell death |
title_short | Ceramide phosphoethanolamine synthase SMSr is a target of caspase-6 during apoptotic cell death |
title_sort | ceramide phosphoethanolamine synthase smsr is a target of caspase-6 during apoptotic cell death |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567093/ https://www.ncbi.nlm.nih.gov/pubmed/28659495 http://dx.doi.org/10.1042/BSR20170867 |
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