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

Tumour-necrosis factor (TNF) receptor-associated factor 2 (TRAF2) is a key component in NF-kappaB signalling triggered by TNF-alpha. Genetic evidence indicates that TRAF2 is necessary for the polyubiquitination of receptor interacting protein 1 (RIP1) that then serves as a platform for recruitment and stimulation of IkappaB kinase, leading to activation of the transcription factor NF-kappaB. 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), 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 IkappaB kinase and IkappaBalpha, and IkappaBalpha degradation, leading to NF-kappaB 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-alpha signalling and the canonical NF-kappaB activation pathway important in inflammatory, antiapoptotic and immune processes.

Pubmed ID: 20577214


  • Alvarez SE
  • Harikumar KB
  • Hait NC
  • Allegood J
  • Strub GM
  • Kim EY
  • Maceyka M
  • Jiang H
  • Luo C
  • Kordula T
  • Milstien S
  • Spiegel S



Publication Data

June 24, 2010

Associated Grants

  • Agency: NIAID NIH HHS, Id: R01 AI050094
  • Agency: NIAID NIH HHS, Id: R01 AI050094-09
  • Agency: NCI NIH HHS, Id: R01 CA061774
  • Agency: NCI NIH HHS, Id: R01 CA061774-15
  • Agency: NCI NIH HHS, Id: R01 CA061774-16
  • Agency: NIAID NIH HHS, Id: R01AI50094
  • Agency: NCI NIH HHS, Id: R01CA61774
  • Agency: NIGMS NIH HHS, Id: R37 GM043880
  • Agency: NIGMS NIH HHS, Id: R37 GM043880-18
  • Agency: NIGMS NIH HHS, Id: R37 GM043880-19
  • Agency: NIGMS NIH HHS, Id: R37 GM043880-20
  • Agency: NIGMS NIH HHS, Id: R37 GM043880-21
  • Agency: NIGMS NIH HHS, Id: R37GM043880
  • Agency: NIAID NIH HHS, Id: U19 AI077435
  • Agency: NIAID NIH HHS, Id: U19 AI077435-020004
  • Agency: NIAID NIH HHS, Id: U19 AI077435-02S10004
  • Agency: NIAID NIH HHS, Id: U19 AI077435-030004
  • Agency: NIAID NIH HHS, Id: U19AI077435

Mesh Terms

  • Animals
  • Biocatalysis
  • Cell Line
  • Enzyme Activation
  • Humans
  • I-kappa B Kinase
  • I-kappa B Proteins
  • Lysine
  • Lysophospholipids
  • Mice
  • Models, Molecular
  • NF-kappa B
  • Phosphorylation
  • Phosphotransferases (Alcohol Group Acceptor)
  • Protein Binding
  • Protein Structure, Tertiary
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Sphingosine
  • Substrate Specificity
  • TNF Receptor-Associated Factor 2
  • Tumor Necrosis Factor-alpha
  • Ubiquitin-Conjugating Enzymes
  • Ubiquitin-Protein Ligases
  • Ubiquitination