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dc.provenanceCONICET-
dc.creatorAlvarez, Sergio Eduardo-
dc.creatorHarikumar, Kuzhuvelil B.-
dc.creatorHait, Nitai C.-
dc.creatorAllegood, Jeremy-
dc.creatorStrub, Graham M.-
dc.creatorKim, Eugene Y.-
dc.creatorMaceycka, Michael-
dc.creatorJiang, Hualiang-
dc.creatorLu, Cheng-
dc.creatorKordula, Tomasz-
dc.creatorMilstien, Sheldon-
dc.creatorSpiegel, Sarah-
dc.date2017-03-31T18:00:41Z-
dc.date2017-03-31T18:00:41Z-
dc.date2010-06-
dc.date2017-03-30T17:43:06Z-
dc.date.accessioned2019-04-29T15:47:52Z-
dc.date.available2019-04-29T15:47:52Z-
dc.date.issued2010-06-
dc.identifierAlvarez, Sergio Eduardo; Harikumar, Kuzhuvelil B.; Hait, Nitai C.; Allegood, Jeremy; Strub, Graham M.; et al.; Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2; Nature Publishing Group; Nature; 465; 7301; 6-2010; 1084-1088-
dc.identifier0028-0836-
dc.identifierhttp://hdl.handle.net/11336/14601-
dc.identifier1476-4687-
dc.identifier.urihttp://rodna.bn.gov.ar:8080/jspui/handle/bnmm/302281-
dc.descriptionTumour-necrosis factor (TNF) receptor-associated factor 2 (TRAF2) is a key component in NF-κB signalling triggered by TNF-α1, 2. Genetic evidence indicates that TRAF2 is necessary for the polyubiquitination of receptor interacting protein 1 (RIP1)3 that then serves as a platform for recruitment and stimulation of IκB kinase, leading to activation of the transcription factor NF-κB. Although TRAF2 is a RING domain ubiquitin ligase, direct evidence that TRAF2 catalyses the ubiquitination of RIP1 is lacking. TRAF2 binds to sphingosine kinase 1 (SphK1)4, one of the isoenzymes that generates the pro-survival lipid mediator sphingosine-1-phosphate (S1P) inside cells. Here we show that SphK1 and the production of S1P is necessary for lysine-63-linked polyubiquitination of RIP1, phosphorylation of IκB kinase and IκBα, and IκBα degradation, leading to NF-κB activation. These responses were mediated by intracellular S1P independently of its cell surface G-protein-coupled receptors. S1P specifically binds to TRAF2 at the amino-terminal RING domain and stimulates its E3 ligase activity. S1P, but not dihydro-S1P, markedly increased recombinant TRAF2-catalysed lysine-63-linked, but not lysine-48-linked, polyubiquitination of RIP1 in vitro in the presence of the ubiquitin conjugating enzymes (E2) UbcH13 or UbcH5a. Our data show that TRAF2 is a novel intracellular target of S1P, and that S1P is the missing cofactor for TRAF2 E3 ubiquitin ligase activity, indicating a new paradigm for the regulation of lysine-63-linked polyubiquitination. These results also highlight the key role of SphK1 and its product S1P in TNF-α signalling and the canonical NF-κB activation pathway important in inflammatory, antiapoptotic and immune processes.-
dc.descriptionFil: Alvarez, Sergio Eduardo. Virginia Commonwealth University. School of Medicine; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina-
dc.descriptionFil: Harikumar, Kuzhuvelil B.. Virginia Commonwealth University. School of Medicine; Estados Unidos-
dc.descriptionFil: Hait, Nitai C.. Virginia Commonwealth University. School of Medicine; Estados Unidos-
dc.descriptionFil: Allegood, Jeremy. Virginia Commonwealth University. School of Medicine; Estados Unidos-
dc.descriptionFil: Strub, Graham M.. Virginia Commonwealth University. School of Medicine; Estados Unidos-
dc.descriptionFil: Kim, Eugene Y.. Virginia Commonwealth University. School of Medicine; Estados Unidos-
dc.descriptionFil: Maceycka, Michael. Virginia Commonwealth University. School of Medicine; Estados Unidos-
dc.descriptionFil: Jiang, Hualiang. Chinese Academy of Sciences. Shangai Institute of Materia Medica. State Key Laboratory of Drug Research; China-
dc.descriptionFil: Lu, Cheng. Chinese Academy of Sciences. Shangai Institute of Materia Medica. State Key Laboratory of Drug Research; China-
dc.descriptionFil: Kordula, Tomasz. Virginia Commonwealth University. School of Medicine; Estados Unidos-
dc.descriptionFil: Milstien, Sheldon. Virginia Commonwealth University. School of Medicine; Estados Unidos-
dc.descriptionFil: Spiegel, Sarah. Virginia Commonwealth University. School of Medicine; Estados Unidos-
dc.formatapplication/pdf-
dc.formatapplication/pdf-
dc.languageeng-
dc.publisherNature Publishing Group-
dc.relationinfo:eu-repo/semantics/altIdentifier/url/http://www.nature.com/nature/journal/v465/n7301/full/nature09128.html-
dc.relationinfo:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1038/nature09128-
dc.rightsinfo:eu-repo/semantics/restrictedAccess-
dc.rightshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/-
dc.sourcereponame:CONICET Digital (CONICET)-
dc.sourceinstname:Consejo Nacional de Investigaciones Científicas y Técnicas-
dc.sourceinstacron:CONICET-
dc.source.urihttp://hdl.handle.net/11336/14601-
dc.subjectNF-kB-
dc.subjectSPHINGOSINE-1-PHOSPHATE-
dc.subjectUBIQUITINATION-
dc.subjectSPHINGOSINE KINASE-
dc.subjectBiología Celular, Microbiología-
dc.subjectCiencias Biológicas-
dc.subjectCIENCIAS NATURALES Y EXACTAS-
dc.titleSphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2-
dc.typeinfo:eu-repo/semantics/article-
dc.typeinfo:eu-repo/semantics/publishedVersion-
dc.typeinfo:ar-repo/semantics/articulo-
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