Sphingolipids: The Oil on the TRAFire That Promotes Inflammation

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

Sphingolipids: The Oil on the TRAFire That Promotes Inflammation

  1. Gennaro Napolitano and
  2. Michael Karin*
  1. 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.
  1. *Corresponding author. E-mail, karinoffice{at}ucsd.edu


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-α, 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 IκB kinase complex and consequently nuclear factor κB. 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.


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

Hepatic TRAF2 Regulates Glucose Metabolism Through Enhancing Glucagon Responses
Z. Chen, L. Sheng, H. Shen, Y. Zhao, S. Wang, R. Brink, and L. Rui
Diabetes 61, 566-573 (1 March 2012)

TANK-binding kinase 1 (TBK1) controls cell survival through PAI-2/serpinB2 and transglutaminase 2
M. Delhase, S.-Y. Kim, H. Lee, A. Naiki-Ito, Y. Chen, E.-R. Ahn, K. Murata, S.-J. Kim, N. Lautsch, K. S. Kobayashi et al.
Proc. Natl. Acad. Sci. USA 109, E177-E186 (24 January 2012)

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882