SPHINGOSINE-1-PHOSPHATE: A MISSING COFACTOR FOR THE E3 UBIQUITIN LIGASE TRAF2

By Sergio E. Alvarez, K. Harikumar, N. Hait, J. Allegood, G. Strub, Eugene Kim, Michael Maceyka, Hualiang Jiang, Cheng Luo, T. Kordula and 2 more. Nature, 2010

745 citations recorded by the source corpus.

Tumour-necrosis factor (TNF) receptor-associated factor 2 (TRAF2) is a key component in NF-κB signalling triggered by TNF-α. 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 IκB kinase, leading to activation of the transcription factor NF-κB. 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 IκB kinase and IκBα, and IκBα degradation, leading to NF-κB 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-α signalling and the canonical NF-κB activation pathway important in inflammatory, antiapoptotic and immune processes.

Subfields: Cancer Research, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/11c4f6befe30deab749e7478a5a6d8961966913f

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In Cancer Research

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Citations in the corpus

• Computational drug discovery (2012, background): “S1P was also found to be a missing cofactor for the E3 ubiquitin ligase TRAF2 [60] .”
• Signaling in innate immunity and inflammation. (2012, background): “Ubiquitylation of RIP1 by the cIAPs and E2 UbcH5 is believed to be important for recruitment of NEMO and TAK1, and subsequently for IKK activation (Varfolomeev et al. 2008; Xu et al. 2009), although TRAF2 ubiquitin ligase activity has been invoked recently as well (Alvarez et al. 2010).”