Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2

Autores
Alvarez, Sergio Eduardo; Harikumar, Kuzhuvelil B.; Hait, Nitai C.; Allegood, Jeremy; Strub, Graham M.; Kim, Eugene Y.; Maceycka, Michael; Jiang, Hualiang; Lu, Cheng; Kordula, Tomasz; Milstien, Sheldon; Spiegel, Sarah
Año de publicación
2010
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Tumour-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.
Fil: 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
Fil: Harikumar, Kuzhuvelil B.. Virginia Commonwealth University. School of Medicine; Estados Unidos
Fil: Hait, Nitai C.. Virginia Commonwealth University. School of Medicine; Estados Unidos
Fil: Allegood, Jeremy. Virginia Commonwealth University. School of Medicine; Estados Unidos
Fil: Strub, Graham M.. Virginia Commonwealth University. School of Medicine; Estados Unidos
Fil: Kim, Eugene Y.. Virginia Commonwealth University. School of Medicine; Estados Unidos
Fil: Maceycka, Michael. Virginia Commonwealth University. School of Medicine; Estados Unidos
Fil: Jiang, Hualiang. Chinese Academy of Sciences. Shangai Institute of Materia Medica. State Key Laboratory of Drug Research; China
Fil: Lu, Cheng. Chinese Academy of Sciences. Shangai Institute of Materia Medica. State Key Laboratory of Drug Research; China
Fil: Kordula, Tomasz. Virginia Commonwealth University. School of Medicine; Estados Unidos
Fil: Milstien, Sheldon. Virginia Commonwealth University. School of Medicine; Estados Unidos
Fil: Spiegel, Sarah. Virginia Commonwealth University. School of Medicine; Estados Unidos
Materia
Nf-Kb
Sphingosine-1-Phosphate
Ubiquitination
Sphingosine Kinase
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/14601

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repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2Alvarez, Sergio EduardoHarikumar, Kuzhuvelil B.Hait, Nitai C.Allegood, JeremyStrub, Graham M.Kim, Eugene Y.Maceycka, MichaelJiang, HualiangLu, ChengKordula, TomaszMilstien, SheldonSpiegel, SarahNf-KbSphingosine-1-PhosphateUbiquitinationSphingosine Kinasehttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Tumour-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.Fil: 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; ArgentinaFil: Harikumar, Kuzhuvelil B.. Virginia Commonwealth University. School of Medicine; Estados UnidosFil: Hait, Nitai C.. Virginia Commonwealth University. School of Medicine; Estados UnidosFil: Allegood, Jeremy. Virginia Commonwealth University. School of Medicine; Estados UnidosFil: Strub, Graham M.. Virginia Commonwealth University. School of Medicine; Estados UnidosFil: Kim, Eugene Y.. Virginia Commonwealth University. School of Medicine; Estados UnidosFil: Maceycka, Michael. Virginia Commonwealth University. School of Medicine; Estados UnidosFil: Jiang, Hualiang. Chinese Academy of Sciences. Shangai Institute of Materia Medica. State Key Laboratory of Drug Research; ChinaFil: Lu, Cheng. Chinese Academy of Sciences. Shangai Institute of Materia Medica. State Key Laboratory of Drug Research; ChinaFil: Kordula, Tomasz. Virginia Commonwealth University. School of Medicine; Estados UnidosFil: Milstien, Sheldon. Virginia Commonwealth University. School of Medicine; Estados UnidosFil: Spiegel, Sarah. Virginia Commonwealth University. School of Medicine; Estados UnidosNature Publishing Group2010-06info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/14601Alvarez, 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; 1084-10880028-08361476-4687enginfo:eu-repo/semantics/altIdentifier/url/http://www.nature.com/nature/journal/v465/n7301/full/nature09128.htmlinfo:eu-repo/semantics/altIdentifier/doi/10.1038/nature09128info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T14:27:20Zoai:ri.conicet.gov.ar:11336/14601instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-15 14:27:20.633CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2
title Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2
spellingShingle Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2
Alvarez, Sergio Eduardo
Nf-Kb
Sphingosine-1-Phosphate
Ubiquitination
Sphingosine Kinase
title_short Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2
title_full Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2
title_fullStr Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2
title_full_unstemmed Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2
title_sort Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2
dc.creator.none.fl_str_mv Alvarez, Sergio Eduardo
Harikumar, Kuzhuvelil B.
Hait, Nitai C.
Allegood, Jeremy
Strub, Graham M.
Kim, Eugene Y.
Maceycka, Michael
Jiang, Hualiang
Lu, Cheng
Kordula, Tomasz
Milstien, Sheldon
Spiegel, Sarah
author Alvarez, Sergio Eduardo
author_facet Alvarez, Sergio Eduardo
Harikumar, Kuzhuvelil B.
Hait, Nitai C.
Allegood, Jeremy
Strub, Graham M.
Kim, Eugene Y.
Maceycka, Michael
Jiang, Hualiang
Lu, Cheng
Kordula, Tomasz
Milstien, Sheldon
Spiegel, Sarah
author_role author
author2 Harikumar, Kuzhuvelil B.
Hait, Nitai C.
Allegood, Jeremy
Strub, Graham M.
Kim, Eugene Y.
Maceycka, Michael
Jiang, Hualiang
Lu, Cheng
Kordula, Tomasz
Milstien, Sheldon
Spiegel, Sarah
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Nf-Kb
Sphingosine-1-Phosphate
Ubiquitination
Sphingosine Kinase
topic Nf-Kb
Sphingosine-1-Phosphate
Ubiquitination
Sphingosine Kinase
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Tumour-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.
Fil: 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
Fil: Harikumar, Kuzhuvelil B.. Virginia Commonwealth University. School of Medicine; Estados Unidos
Fil: Hait, Nitai C.. Virginia Commonwealth University. School of Medicine; Estados Unidos
Fil: Allegood, Jeremy. Virginia Commonwealth University. School of Medicine; Estados Unidos
Fil: Strub, Graham M.. Virginia Commonwealth University. School of Medicine; Estados Unidos
Fil: Kim, Eugene Y.. Virginia Commonwealth University. School of Medicine; Estados Unidos
Fil: Maceycka, Michael. Virginia Commonwealth University. School of Medicine; Estados Unidos
Fil: Jiang, Hualiang. Chinese Academy of Sciences. Shangai Institute of Materia Medica. State Key Laboratory of Drug Research; China
Fil: Lu, Cheng. Chinese Academy of Sciences. Shangai Institute of Materia Medica. State Key Laboratory of Drug Research; China
Fil: Kordula, Tomasz. Virginia Commonwealth University. School of Medicine; Estados Unidos
Fil: Milstien, Sheldon. Virginia Commonwealth University. School of Medicine; Estados Unidos
Fil: Spiegel, Sarah. Virginia Commonwealth University. School of Medicine; Estados Unidos
description Tumour-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.
publishDate 2010
dc.date.none.fl_str_mv 2010-06
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/14601
Alvarez, 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
0028-0836
1476-4687
url http://hdl.handle.net/11336/14601
identifier_str_mv Alvarez, 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
0028-0836
1476-4687
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://www.nature.com/nature/journal/v465/n7301/full/nature09128.html
info:eu-repo/semantics/altIdentifier/doi/10.1038/nature09128
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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