Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2

doi:10.1038/nature09128

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	Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2
	Alvarez, Sergio E.1,2; Harikumar, Kuzhuvelil B.1,2; Hait, Nitai C.1,2; Allegood, Jeremy 1,2; Strub, Graham M.1,2; Kim, Eugene Y.1,2; Maceyka, Michael 1,2; Jiang, Hualiang3 ; Luo, Cheng3 ; Kordula, Tomasz 1,2
刊名	NATURE
	2010-06-24
卷号	465 期号:7301 页码:1084-U149
ISSN号	0028-0836
DOI	10.1038/nature09128
文献子类	Article
英文摘要	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.
资助项目	National Institute of Health[R37GM043880] ; National Institute of Health[R01CA61774] ; National Institute of Health[R01AI50094] ; National Institute of Health[U19AI077435] ; Ministry of Scientific and Technology of China[2009CB918502]
WOS关键词	NF-KAPPA-B ; SPHINGOSINE 1-PHOSPHATE ; ENDOTHELIAL-CELLS ; TNF-ALPHA ; ACTIVATION ; POLYUBIQUITIN ; KINASE-1 ; RIP1 ; IKK ; PHOSPHORYLATION
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000279056900054
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/278868]
专题	药物发现与设计中心中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Spiegel, Sarah
作者单位	1.Virginia Commonwealth Univ, Dept Biochem & Mol Biophys, Sch Med, Richmond, VA 23298 USA; 2.Virginia Commonwealth Univ, Massey Canc Ctr, Sch Med, Richmond, VA 23298 USA; 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Alvarez, Sergio E.,Harikumar, Kuzhuvelil B.,Hait, Nitai C.,et al. Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2[J]. NATURE,2010,465(7301):1084-U149.
APA	Alvarez, Sergio E..,Harikumar, Kuzhuvelil B..,Hait, Nitai C..,Allegood, Jeremy.,Strub, Graham M..,...&Spiegel, Sarah.(2010).Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2.NATURE,465(7301),1084-U149.
MLA	Alvarez, Sergio E.,et al."Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2".NATURE 465.7301(2010):1084-U149.