Research ArticleImmunology

Two Mechanistically and Temporally Distinct NF-κB Activation Pathways in IL-1 Signaling

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Science Signaling  20 Oct 2009:
Vol. 2, Issue 93, pp. ra66
DOI: 10.1126/scisignal.2000387

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A One-Two Punch

Members of the interleukin-1 (IL-1) family of cytokines stimulate proinflammatory responses through their activation of the transcription factors nuclear factor κB (NF-κB) and activating protein 1 (AP-1). The binding of IL-1 to its receptor complex triggers the activation of the E3 ubiquitin ligase and scaffold protein TRAF6 and its association with the mitogen-activated protein kinase (MAPK) kinase kinase (MAP3K) TAK1, which leads to the activation of NF-κB. Another MAP3K, MEKK3, is also involved in IL-1–mediated activation of NF-κB, but how TAK1 and MEKK3 might physically or functionally interact has been unclear. Yamazaki et al. showed that early IL-1 signaling induced the formation of a transient complex of TRAF6, TAK1, and MEKK3. Formation of this complex, which was dependent on TRAF6-mediated ubiquitination of TAK1, led to NF-κB activation. In a later phase of IL-1 signaling, TRAF6 activated NF-κB in a MEKK3-dependent, TAK1-independent manner. Together, these two pathways resulted in the prolonged activation of NF-κB required to trigger an effective proinflammatory response.

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