Sphingomyelin synthase-related protein SMSr is a suppressor of ceramide-induced mitochondrial apoptosis
DC Element | Wert | Sprache |
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dc.contributor.author | Tafesse, Fikadu G. | |
dc.contributor.author | Vacaru, Ana M. | |
dc.contributor.author | Bosma, Elleke F. | |
dc.contributor.author | Hermansson, Martin | |
dc.contributor.author | Jain, Amrita | |
dc.contributor.author | Hilderink, Angelika | |
dc.contributor.author | Somerharju, Pentti | |
dc.contributor.author | Holthuis, Joost C. M. | |
dc.date.accessioned | 2021-12-23T16:20:30Z | - |
dc.date.available | 2021-12-23T16:20:30Z | - |
dc.date.issued | 2014 | |
dc.identifier.issn | 00219533 | |
dc.identifier.uri | https://osnascholar.ub.uni-osnabrueck.de/handle/unios/13479 | - |
dc.description.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 alpha-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. | |
dc.description.sponsorship | European UnionEuropean Commission [289278]; Dutch Organization of Sciences [NWO-CW ECHO 700.59.002]; Deutsche ForschungsgemeinschaftGerman Research Foundation (DFG) [Sonderforschungsbereich/SFB944]; This work was supported by the European Union (7th FP Marie-Curie ITN ``Sphingonet'' 289278), the Dutch Organization of Sciences (NWO-CW ECHO 700.59.002); and the Deutsche Forschungsgemeinschaft Sonderforschungsbereich/SFB944, project P14 to J.C.M.H. | |
dc.language.iso | en | |
dc.publisher | COMPANY OF BIOLOGISTS LTD | |
dc.relation.ispartof | JOURNAL OF CELL SCIENCE | |
dc.subject | ALKALINE CERAMIDASE | |
dc.subject | BIOSYNTHESIS | |
dc.subject | Cell Biology | |
dc.subject | Ceramide homeostasis | |
dc.subject | Ceramide phosphoethanolamine | |
dc.subject | COMPLEX | |
dc.subject | ENDOPLASMIC-RETICULUM | |
dc.subject | HELA-CELLS | |
dc.subject | MEMBRANE | |
dc.subject | METABOLISM | |
dc.subject | Mitochondrial apoptosis | |
dc.subject | PROGRAMMED CELL-DEATH | |
dc.subject | RADIATION-INDUCED APOPTOSIS | |
dc.subject | SAM domain | |
dc.subject | SPHINGOLIPIDS | |
dc.subject | Sphingomyelin synthase-related protein | |
dc.title | Sphingomyelin synthase-related protein SMSr is a suppressor of ceramide-induced mitochondrial apoptosis | |
dc.type | journal article | |
dc.identifier.doi | 10.1242/jcs.138933 | |
dc.identifier.isi | ISI:000329789200019 | |
dc.description.volume | 127 | |
dc.description.issue | 2 | |
dc.description.startpage | 445 | |
dc.description.endpage | 454 | |
dc.contributor.orcid | 0000-0003-3387-8365 | |
dc.contributor.orcid | 0000-0001-6189-7753 | |
dc.contributor.orcid | 0000-0002-8575-4164 | |
dc.contributor.orcid | 0000-0001-7976-8992 | |
dc.contributor.orcid | 0000-0001-8912-1586 | |
dc.contributor.researcherid | B-7854-2008 | |
dc.contributor.researcherid | AAR-7370-2021 | |
dc.contributor.researcherid | AAL-9157-2020 | |
dc.contributor.researcherid | R-1749-2018 | |
dc.identifier.eissn | 14779137 | |
dc.publisher.place | BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND | |
dcterms.isPartOf.abbreviation | J. Cell Sci. | |
dcterms.oaStatus | Green Submitted, Bronze |
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geprüft am 29.05.2024