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Sci. Signal., 28 September 2010
Vol. 3, Issue 141, p. pe34
[DOI: 10.1126/scisignal.3141pe34]

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Sphingolipids: The Oil on the TRAFire That Promotes Inflammation

Gennaro Napolitano and Michael Karin*

Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.

Abstract: Tumor necrosis factor receptor (TNFR)–associated factors (TRAFs) control inflammatory and immune responses by acting downstream of TNFRs and Toll-like receptors (TLRs). TRAF2 in particular has been extensively studied for its involvement in signaling by TNF-{alpha}, the classic inflammatory cytokine. Because it has a RING finger, it has been suggested that TRAF2 acts as an E3 ubiquitin ligase that catalyzes the noncanonical Lys-63 (K63)–linked polyubiquitination of receptor-induced protein 1 (RIP1), which is an essential event in the activation of the I{kappa}B kinase complex and consequently nuclear factor {kappa}B. Furthermore, TRAF2 itself is subject to K63-linked polyubiquitination, a modification that is rapidly induced upon receptor ligation and was interpreted to be the result of self-ubiquitination. However, formal evidence that TRAF2 is an active E3 ubiquitin ligase was lacking. New evidence shows that sphingosine-1-phosphate (S1P), a sphingolipid that is synthesized during inflammatory responses, is an essential cofactor for TRAF2 ubiquitin ligase activity. S1P binds to TRAF2 and promotes TRAF2-mediated K63-linked RIP1 polyubiquitination, providing direct evidence that TRAF2 is an active E3 ubiquitin ligase and also introducing lipid second messengers into the realm of TNFR and TLR signaling.

* Corresponding author. E-mail, karinoffice{at}ucsd.edu

Citation: G. Napolitano, M. Karin, Sphingolipids: The Oil on the TRAFire That Promotes Inflammation. Sci. Signal. 3, pe34 (2010).

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