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
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/14601
Ver los metadatos del registro completo
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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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1846082727630077952 |
score |
13.22299 |