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Steno Diabetes Center (H.F., S.G.R., P.E.H., T.M.-P., N.B.), 2820 Gentofte, Denmark; Medical Research Council Protein Phosphorylation Unit (H.M., P.C.), School of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, United Kingdom; and Department of Molecular Medicine (T.M.-P.), Karolinska Institute, Stockholm, Sweden
Address all correspondence to: Nils Billestrup, Steno Diabetes Center, Niels Steensens Vej 2, 2820 Gentofte, Denmark. E-mail: NBil{at}steno.dk.Address reprint requests to: Helle Frobøse, Steno Diabetes Center, Niels Steensens Vej 2, 2820 Gentofte, Denmark.
IL-1 plays a major role in inflammation and autoimmunity through activation of nuclear factor 
B (NFB) and MAPKs. Although a great deal is known about the mechanism of activation of NFB and MAPKs by IL-1, much less is known about the down-regulation of this pathway. Suppressor of cytokine signaling (SOCS)-3 was shown to inhibit IL-1-induced transcription and activation of NFB and the MAPKs JNK and p38, but the mechanism is unknown. We show here that SOCS-3 inhibits NFB-dependent transcription induced by overexpression of the upstream IL-1 signaling molecules MyD88, IL-1R-activated kinase 1, TNF receptor-associated factor (TRAF)6, and TGFß-activated kinase (TAK)1, but not when the MAP3K MAPK/ERK kinase kinase-1 is used instead of TAK1, indicating that the target for SOCS-3 is the TRAF6/TAK1 signaling complex. By coimmunoprecipitation, it was shown that SOCS-3 inhibited the association between TRAF6 and TAK1 and that SOCS-3 coimmunoprecipitated with TAK1 and TRAF6. Furthermore, SOCS-3 inhibited the IL-1-induced catalytic activity of TAK1. Because ubiquitination of TRAF6 is required for activation of TAK1, we analyzed the role of SOCS-3 on TRAF6 ubiquitination and found that SOCS-3 inhibited ubiquitin modification of TRAF6. These results indicate that SOCS-3 inhibits IL-1 signal transduction by inhibiting ubiquitination of TRAF6, thus preventing association and activation of TAK1.
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