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Sci. Signal., 29 June 2010
Vol. 3, Issue 128, p. ec195
[DOI: 10.1126/scisignal.3128ec195]

EDITORS' CHOICE

NF-{kappa}B Signaling Sphingolipids for Ubiquitination

Wei Wong

Science Signaling, AAAS, Washington, DC 20005, USA

Binding of tumor necrosis factor–{alpha} (TNF-{alpha}) to its receptor triggers the Lys63 polyubiquitination of RIP1 (receptor interacting protein 1) by the ubiquitin E3 ligase TRAF2 (TNF receptor–associated factor 2). The inhibitor {kappa}B kinase (IKK) complex is recruited to polyubiquitinated RIP1, where two of its subunits (IKK{alpha} and IKKβ) are phosphorylated and activated. Phosphorylation of I{kappa}B{alpha} by the IKK complex triggers its degradation, thereby releasing the nuclear factor {kappa}B (NF-{kappa}B) subunits p60 and p50, which translocate to the nucleus and activate transcription of target genes. TRAF2 interacts with sphingosine kinase 1 (SphK1), which phosphorylates the sphingolipid sphingosine to generate sphingosine 1-phosphate (S1P). Although the interaction of SphK1 with TRAF2 was known to promote activation of NF-{kappa}B, the precise role of SphK1 in NF-{kappa}B signal transduction was unclear. Alvarez et al. found that lack of SphK1, whether through depletion by small interfering RNAs (siRNAs), genetic deficiency, or pharmacological inhibition, decreased phosphorylation of IKK{alpha}, IKKβ, and I{kappa}B{alpha} in response to TNF-{alpha}. Sphk1–/– mouse embryo fibroblasts (MEFs) also showed reduced TNF-{alpha}–induced translocation of p65 to the nucleus, a defect that was rescued by expression of wild-type, but not catalytically inactive, SphK1. S1P produced by SphK1 can be released by cells and act on G protein–coupled receptors. However, treatment of cells with exogenous S1P or a reagent that activates S1P1 and S1P3 receptors (dihydro-S1P) did not alter phosphorylation and degradation of I{kappa}B{alpha}, suggesting that S1P did not act through its cell surface receptors to regulate NF-{kappa}B signaling. Lys63 polyubiquitination of RIP1 in TNF-{alpha}–treated cells was reduced by knockdown of SphK1 by siRNA, and in vitro assays indicated that TRAF2 ubiquitinated RIP1 only in the presence of S1P. S1P directly bound to TRAF2 at its RING domain and was detected in TRAF2 immunoprecipitates, an association that was increased by TNF-{alpha} treatment. The authors note that because Lys63 polyubiquitination of RIP1 promotes cell survival, their finding that S1P is a cofactor for TRAF2 helps to explain the previously reported antiapoptotic effects of S1P and SphK1.

S. E. Alvarez, K. B. Harikumar, N. C. Hait, J. Allegood, G. M. Strub, E. Y. Kim, M. Maceyka, H. Jiang, C. Luo, T. Kordula, S. Milstien, S. Spiegel, Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2. Nature 465, 1084–1088 (2010). [PubMed]

Citation: W. Wong, Sphingolipids for Ubiquitination. Sci. Signal. 3, ec195 (2010).



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