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

摘要: Tumour-necrosis factor (TNF) receptor-associated 2 (TRAF2) is a key component in NF-kappaB signalling triggered by TNF-alpha. Genetic evidence indicates that TRAF2 necessary for the polyubiquitination of receptor interacting protein 1 (RIP1) then serves as platform recruitment and stimulation IkappaB kinase, leading to activation transcription NF-kappaB. Although RING domain ubiquitin ligase, direct catalyses ubiquitination RIP1 lacking. binds sphingosine kinase (SphK1), one isoenzymes generates pro-survival lipid mediator sphingosine-1-phosphate (S1P) inside cells. Here we show SphK1 production S1P lysine-63-linked RIP1, phosphorylation IkappaBalpha, IkappaBalpha degradation, activation. These responses were mediated intracellular independently its cell surface G-protein-coupled receptors. specifically at amino-terminal stimulates E3 ligase activity. S1P, but not dihydro-S1P, markedly increased recombinant TRAF2-catalysed lysine-63-linked, lysine-48-linked, vitro presence conjugating enzymes (E2) UbcH13 or UbcH5a. Our data novel target missing cofactor activity, indicating new paradigm regulation polyubiquitination. results also highlight role product TNF-alpha canonical pathway important inflammatory, antiapoptotic immune processes.