Suppressor of cytokine signaling-3 inhibits interleukin-1 signaling by targeting the TRAF-6/TAK1 complex

Helle Frobøse, Sif Groth Rønn, Peter E. Heding, Heidi Mendoza, Philip Cohen, Thomas Mandrup-Poulsen, Nils Billestrup (Lead / Corresponding author)

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    Abstract

    IL-1 plays a major role in inflammation and autoimmunity through activation of nuclear factor κ B (NFκB) and MAPKs. Although a great deal is known about the mechanism of activation of NFκB and MAPKs by IL-1, much less is known about the downregulation of this pathway. Suppressor of cytokine signaling (SOCS)-3 was shown to inhibit IL-1-induced transcription and activation of NFκB and the MAPKs JNK and p38, but the mechanism is unknown. We show here that SOCS-3 inhibits NFκB-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 TGFβ-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.

    Original languageEnglish
    Pages (from-to)1587-1596
    Number of pages10
    JournalMolecular Endocrinology
    Volume20
    Issue number7
    DOIs
    Publication statusPublished - 5 Jul 2006

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  • Cite this

    Frobøse, H., Rønn, S. G., Heding, P. E., Mendoza, H., Cohen, P., Mandrup-Poulsen, T., & Billestrup, N. (2006). Suppressor of cytokine signaling-3 inhibits interleukin-1 signaling by targeting the TRAF-6/TAK1 complex. Molecular Endocrinology, 20(7), 1587-1596. https://doi.org/10.1210/me.2005-0301