Sphingomyelin synthase-related protein SMSr controls ceramide homeostasis in the ER
Ceramides are central intermediates of sphingolipid metabolism with critical functions in cell organization and survival. They are synthesized on the cytosolic surface of the endoplasmic reticulum (ER) and transported by ceramide transfer protein to the Golgi for conversion to sphingomyelin (SM) by...
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| Veröffentlicht in: | The Journal of cell biology 2009-06, Vol.185 (6), p.1013-1027 |
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| creator | Vacaru, Ana M Tafesse, Fikadu G Ternes, Philipp Kondylis, Vangelis Hermansson, Martin Brouwers, Jos F.H.M Somerharju, Pentti Rabouille, Catherine Holthuis, Joost C.M |
| description | Ceramides are central intermediates of sphingolipid metabolism with critical functions in cell organization and survival. They are synthesized on the cytosolic surface of the endoplasmic reticulum (ER) and transported by ceramide transfer protein to the Golgi for conversion to sphingomyelin (SM) by SM synthase SMS1. In this study, we report the identification of an SMS1-related (SMSr) enzyme, which catalyses the synthesis of the SM analogue ceramide phosphoethanolamine (CPE) in the ER lumen. Strikingly, SMSr produces only trace amounts of CPE, i.e., 300-fold less than SMS1-derived SM. Nevertheless, blocking its catalytic activity causes a substantial rise in ER ceramide levels and a structural collapse of the early secretory pathway. We find that the latter phenotype is not caused by depletion of CPE but rather a consequence of ceramide accumulation in the ER. Our results establish SMSr as a key regulator of ceramide homeostasis that seems to operate as a sensor rather than a converter of ceramides in the ER. |
| doi_str_mv | 10.1083/jcb.200903152 |
| format | Article |
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They are synthesized on the cytosolic surface of the endoplasmic reticulum (ER) and transported by ceramide transfer protein to the Golgi for conversion to sphingomyelin (SM) by SM synthase SMS1. In this study, we report the identification of an SMS1-related (SMSr) enzyme, which catalyses the synthesis of the SM analogue ceramide phosphoethanolamine (CPE) in the ER lumen. Strikingly, SMSr produces only trace amounts of CPE, i.e., 300-fold less than SMS1-derived SM. Nevertheless, blocking its catalytic activity causes a substantial rise in ER ceramide levels and a structural collapse of the early secretory pathway. We find that the latter phenotype is not caused by depletion of CPE but rather a consequence of ceramide accumulation in the ER. Our results establish SMSr as a key regulator of ceramide homeostasis that seems to operate as a sensor rather than a converter of ceramides in the ER.</description><identifier>ISSN: 0021-9525</identifier><identifier>EISSN: 1540-8140</identifier><identifier>DOI: 10.1083/jcb.200903152</identifier><identifier>PMID: 19506037</identifier><identifier>CODEN: JCLBA3</identifier><language>eng</language><publisher>United States: The Rockefeller University Press</publisher><subject>Active sites ; Animals ; Biochemistry ; Cell Line ; Cell membranes ; Cellular biology ; Ceramides ; Ceramides - metabolism ; Delta cells ; Drosophila ; Drosophila melanogaster - cytology ; Drosophila melanogaster - metabolism ; Endoplasmic Reticulum - metabolism ; Endoplasmic Reticulum - ultrastructure ; Enzymes ; Golgi Apparatus - metabolism ; HeLa cells ; Homeostasis ; Humans ; Lipids ; Membrane Proteins - classification ; Membrane Proteins - genetics ; Membrane Proteins - metabolism ; Metabolism ; Nerve Tissue Proteins - classification ; Nerve Tissue Proteins - genetics ; Nerve Tissue Proteins - metabolism ; Phylogeny ; Proteins ; RNA Interference ; Secretory Pathway - physiology ; Sphingolipids ; Sphingomyelins - metabolism ; Transferases (Other Substituted Phosphate Groups) - classification ; Transferases (Other Substituted Phosphate Groups) - genetics ; Transferases (Other Substituted Phosphate Groups) - metabolism</subject><ispartof>The Journal of cell biology, 2009-06, Vol.185 (6), p.1013-1027</ispartof><rights>Copyright Rockefeller University Press Jun 15, 2009</rights><rights>2009 Vacaru et al. 2009</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c524t-365f02245575b34310e28a8566de6ae95c3c5b961d554d8d34ad16842954867a3</citedby><cites>FETCH-LOGICAL-c524t-365f02245575b34310e28a8566de6ae95c3c5b961d554d8d34ad16842954867a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,777,781,882,27905,27906</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19506037$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Vacaru, Ana M</creatorcontrib><creatorcontrib>Tafesse, Fikadu G</creatorcontrib><creatorcontrib>Ternes, Philipp</creatorcontrib><creatorcontrib>Kondylis, Vangelis</creatorcontrib><creatorcontrib>Hermansson, Martin</creatorcontrib><creatorcontrib>Brouwers, Jos F.H.M</creatorcontrib><creatorcontrib>Somerharju, Pentti</creatorcontrib><creatorcontrib>Rabouille, Catherine</creatorcontrib><creatorcontrib>Holthuis, Joost C.M</creatorcontrib><title>Sphingomyelin synthase-related protein SMSr controls ceramide homeostasis in the ER</title><title>The Journal of cell biology</title><addtitle>J Cell Biol</addtitle><description>Ceramides are central intermediates of sphingolipid metabolism with critical functions in cell organization and survival. They are synthesized on the cytosolic surface of the endoplasmic reticulum (ER) and transported by ceramide transfer protein to the Golgi for conversion to sphingomyelin (SM) by SM synthase SMS1. In this study, we report the identification of an SMS1-related (SMSr) enzyme, which catalyses the synthesis of the SM analogue ceramide phosphoethanolamine (CPE) in the ER lumen. Strikingly, SMSr produces only trace amounts of CPE, i.e., 300-fold less than SMS1-derived SM. Nevertheless, blocking its catalytic activity causes a substantial rise in ER ceramide levels and a structural collapse of the early secretory pathway. We find that the latter phenotype is not caused by depletion of CPE but rather a consequence of ceramide accumulation in the ER. Our results establish SMSr as a key regulator of ceramide homeostasis that seems to operate as a sensor rather than a converter of ceramides in the ER.</description><subject>Active sites</subject><subject>Animals</subject><subject>Biochemistry</subject><subject>Cell Line</subject><subject>Cell membranes</subject><subject>Cellular biology</subject><subject>Ceramides</subject><subject>Ceramides - metabolism</subject><subject>Delta cells</subject><subject>Drosophila</subject><subject>Drosophila melanogaster - cytology</subject><subject>Drosophila melanogaster - metabolism</subject><subject>Endoplasmic Reticulum - metabolism</subject><subject>Endoplasmic Reticulum - ultrastructure</subject><subject>Enzymes</subject><subject>Golgi Apparatus - metabolism</subject><subject>HeLa cells</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Lipids</subject><subject>Membrane Proteins - classification</subject><subject>Membrane Proteins - genetics</subject><subject>Membrane Proteins - metabolism</subject><subject>Metabolism</subject><subject>Nerve Tissue Proteins - classification</subject><subject>Nerve Tissue Proteins - genetics</subject><subject>Nerve Tissue Proteins - metabolism</subject><subject>Phylogeny</subject><subject>Proteins</subject><subject>RNA Interference</subject><subject>Secretory Pathway - physiology</subject><subject>Sphingolipids</subject><subject>Sphingomyelins - metabolism</subject><subject>Transferases (Other Substituted Phosphate Groups) - classification</subject><subject>Transferases (Other Substituted Phosphate Groups) - genetics</subject><subject>Transferases (Other Substituted Phosphate Groups) - metabolism</subject><issn>0021-9525</issn><issn>1540-8140</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkc2P0zAQxS0EYruFI0cg4sAty_hjHOeyElrtAtIiJMKeLTeZNqmSuNguUv97vGpVPk5zeD89vXmPsVccrjgY-WHbrq4EQA2So3jCFhwVlIYreMoWAIKXNQq8YJcxbgFAVUo-Zxe8RtAgqwVrml0_zBs_HWgc5iIe5tS7SGWg0SXqil3wibLQfG1C0fo5BT_GoqXgpqGjovcT-ZhcHGKRqdRTcfv9BXu2dmOkl6e7ZA93tz9uPpf33z59ufl4X7YoVCqlxjUIoRArXEklOZAwzqDWHWlHNbayxVWteYeoOtNJ5TqujRI1KqMrJ5fs-ui7268m6lrK6dxod2GYXDhY7wb7rzIPvd34X1ZUnGvAbPD-ZBD8zz3FZKchtjSObia_j1ZX0iiDkMF3_4Fbvw9zfs4KXnGBBh6h8gi1wccYaH1OwsE-bmXzVva8Vebf_B3_D30aJwOvj8A2Jh_OusjJK5kLW7K3R33tvHWbMET70AjgErhWKjclfwPZ3qHw</recordid><startdate>20090615</startdate><enddate>20090615</enddate><creator>Vacaru, Ana M</creator><creator>Tafesse, Fikadu G</creator><creator>Ternes, Philipp</creator><creator>Kondylis, Vangelis</creator><creator>Hermansson, Martin</creator><creator>Brouwers, Jos F.H.M</creator><creator>Somerharju, Pentti</creator><creator>Rabouille, Catherine</creator><creator>Holthuis, Joost C.M</creator><general>The Rockefeller University Press</general><general>Rockefeller University Press</general><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20090615</creationdate><title>Sphingomyelin synthase-related protein SMSr controls ceramide homeostasis in the ER</title><author>Vacaru, Ana M ; Tafesse, Fikadu G ; Ternes, Philipp ; Kondylis, Vangelis ; Hermansson, Martin ; Brouwers, Jos F.H.M ; Somerharju, Pentti ; Rabouille, Catherine ; Holthuis, Joost C.M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c524t-365f02245575b34310e28a8566de6ae95c3c5b961d554d8d34ad16842954867a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Active sites</topic><topic>Animals</topic><topic>Biochemistry</topic><topic>Cell Line</topic><topic>Cell membranes</topic><topic>Cellular biology</topic><topic>Ceramides</topic><topic>Ceramides - metabolism</topic><topic>Delta cells</topic><topic>Drosophila</topic><topic>Drosophila melanogaster - cytology</topic><topic>Drosophila melanogaster - metabolism</topic><topic>Endoplasmic Reticulum - metabolism</topic><topic>Endoplasmic Reticulum - ultrastructure</topic><topic>Enzymes</topic><topic>Golgi Apparatus - metabolism</topic><topic>HeLa cells</topic><topic>Homeostasis</topic><topic>Humans</topic><topic>Lipids</topic><topic>Membrane Proteins - classification</topic><topic>Membrane Proteins - genetics</topic><topic>Membrane Proteins - metabolism</topic><topic>Metabolism</topic><topic>Nerve Tissue Proteins - classification</topic><topic>Nerve Tissue Proteins - genetics</topic><topic>Nerve Tissue Proteins - metabolism</topic><topic>Phylogeny</topic><topic>Proteins</topic><topic>RNA Interference</topic><topic>Secretory Pathway - physiology</topic><topic>Sphingolipids</topic><topic>Sphingomyelins - metabolism</topic><topic>Transferases (Other Substituted Phosphate Groups) - classification</topic><topic>Transferases (Other Substituted Phosphate Groups) - genetics</topic><topic>Transferases (Other Substituted Phosphate Groups) - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Vacaru, Ana M</creatorcontrib><creatorcontrib>Tafesse, Fikadu G</creatorcontrib><creatorcontrib>Ternes, Philipp</creatorcontrib><creatorcontrib>Kondylis, Vangelis</creatorcontrib><creatorcontrib>Hermansson, Martin</creatorcontrib><creatorcontrib>Brouwers, Jos F.H.M</creatorcontrib><creatorcontrib>Somerharju, Pentti</creatorcontrib><creatorcontrib>Rabouille, Catherine</creatorcontrib><creatorcontrib>Holthuis, Joost C.M</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of cell biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Vacaru, Ana M</au><au>Tafesse, Fikadu G</au><au>Ternes, Philipp</au><au>Kondylis, Vangelis</au><au>Hermansson, Martin</au><au>Brouwers, Jos F.H.M</au><au>Somerharju, Pentti</au><au>Rabouille, Catherine</au><au>Holthuis, Joost C.M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Sphingomyelin synthase-related protein SMSr controls ceramide homeostasis in the ER</atitle><jtitle>The Journal of cell biology</jtitle><addtitle>J Cell Biol</addtitle><date>2009-06-15</date><risdate>2009</risdate><volume>185</volume><issue>6</issue><spage>1013</spage><epage>1027</epage><pages>1013-1027</pages><issn>0021-9525</issn><eissn>1540-8140</eissn><coden>JCLBA3</coden><abstract>Ceramides are central intermediates of sphingolipid metabolism with critical functions in cell organization and survival. They are synthesized on the cytosolic surface of the endoplasmic reticulum (ER) and transported by ceramide transfer protein to the Golgi for conversion to sphingomyelin (SM) by SM synthase SMS1. In this study, we report the identification of an SMS1-related (SMSr) enzyme, which catalyses the synthesis of the SM analogue ceramide phosphoethanolamine (CPE) in the ER lumen. Strikingly, SMSr produces only trace amounts of CPE, i.e., 300-fold less than SMS1-derived SM. Nevertheless, blocking its catalytic activity causes a substantial rise in ER ceramide levels and a structural collapse of the early secretory pathway. We find that the latter phenotype is not caused by depletion of CPE but rather a consequence of ceramide accumulation in the ER. Our results establish SMSr as a key regulator of ceramide homeostasis that seems to operate as a sensor rather than a converter of ceramides in the ER.</abstract><cop>United States</cop><pub>The Rockefeller University Press</pub><pmid>19506037</pmid><doi>10.1083/jcb.200903152</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Active sites Animals Biochemistry Cell Line Cell membranes Cellular biology Ceramides Ceramides - metabolism Delta cells Drosophila Drosophila melanogaster - cytology Drosophila melanogaster - metabolism Endoplasmic Reticulum - metabolism Endoplasmic Reticulum - ultrastructure Enzymes Golgi Apparatus - metabolism HeLa cells Homeostasis Humans Lipids Membrane Proteins - classification Membrane Proteins - genetics Membrane Proteins - metabolism Metabolism Nerve Tissue Proteins - classification Nerve Tissue Proteins - genetics Nerve Tissue Proteins - metabolism Phylogeny Proteins RNA Interference Secretory Pathway - physiology Sphingolipids Sphingomyelins - metabolism Transferases (Other Substituted Phosphate Groups) - classification Transferases (Other Substituted Phosphate Groups) - genetics Transferases (Other Substituted Phosphate Groups) - metabolism |
| title | Sphingomyelin synthase-related protein SMSr controls ceramide homeostasis in the ER |
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