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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...

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Autores principales: Cabukusta, Birol, Nettebrock, Niclas T., Kol, Matthijs, Hilderink, Angelika, Tafesse, Fikadu G., Holthuis, Joost C.M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2017
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.
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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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