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Sphingosine‐1‐Phosphate: a missing cofactor for lysine 63‐linked poly‐ubiquitinations in signaling by pro‐inflammatory cytokines

Sphingosine kinase 1, one of the isoenzymes that produce the potent bioactive lipid mediator sphingosine‐1‐phosphate (S1P), has long been implicated in the actions of pro‐inflammatory cytokines. Yet its molecular mechanisms of action have largely remained unclear. We have recently shown that SphK1 and production of S1P is necessary for TNF‐alpha‐induced Lys 63‐linked polyubiquitination of RIP1, phosphorylation of IKK and IκBα, and IκBα degradation, leading to NF‐κB activation (Nature 465:1084, 2010). Surprisingly, these responses were mediated by intracellular S1P independently of its cell surface G protein‐coupled receptors. S1P specifically binds to and stimulates the E3 ligase activity of TNF receptor‐associated factor 2 (TRAF2) a key component in NF‐κB signaling triggered by TNFα. S1P, but not dihydro‐S1P, dramatically increased recombinant TRAF2‐catalyzed Lys 63‐ but not Lys 48‐linked polyubiquitination of RIP1 in vitro. Our data reveal that TRAF2 is a novel intracellular target of S1P, and that S1P is the missing co‐factor for TRAF2 E3 ubiquitin ligase activity, providing a mechanistic explanation for the key role of SphK1 and its product S1P in TNF‐α signaling and the canonical NF‐κB activation pathway important in inflammatory, anti‐apoptotic, and immune processes. We have found that S1P is also a cofactor for some other ubiquitin ligases that are critical for signaling by the pro‐inflammatory cytokine IL‐1. Taken together, our results suggest a new paradigm for regulation of Lys 63‐linked polyubiquitination signaling by S1P.