期刊
NATURE
卷 465, 期 7301, 页码 1084-U149出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature09128
关键词
-
资金
- National Institute of Health [R37GM043880, R01CA61774, R01AI50094, U19AI077435]
- Ministry of Scientific and Technology of China [2009CB918502]
Tumour-necrosis factor (TNF) receptor-associated factor 2 (TRAF2) is a key component in NF-kappa B signalling triggered by TNF-alpha(1,2). Genetic evidence indicates that TRAF2 is necessary for the polyubiquitination of receptor interacting protein 1 (RIP1)(3) that then serves as a platform for recruitment and stimulation of I kappa B kinase, leading to activation of the transcription factor NF-kappa B. 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)(4), 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 I kappa B kinase and I kappa B alpha, and I kappa B alpha degradation, leading to NF-kappa B 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-alpha signalling and the canonical NF-kappa B activation pathway important in inflammatory, antiapoptotic and immune processes.
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