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Lys63-linked polyubiquitination of IRAK-1 is required for interleukin-1 receptor- and toll-like receptor-mediated NF-kappaB activation.

Stimulation through the interleukin-1 receptor (IL-1R) and some Toll-like receptors (TLRs) induces ubiquitination of TRAF6 and IRAK-1, signaling components required for NF-kappaB and mitogen-activated protein kinase activation. Here we show that although TRAF6 and IRAK-1 acquired Lys63 (K63)-linked polyubiquitin chains upon IL-1 stimulation, only ubiquitinated IRAK-1 bound NEMO, the regulatory subunit of IkappaB kinase (IKK). The sites of IRAK-1 ubiquitination were mapped to Lys134 and Lys180, and arginine substitution of these residues impaired IL-1R/TLR-mediated IRAK-1 ubiquitination, NEMO binding, and NF-kappaB activation. K63-linked ubiquitination of IRAK-1 required enzymatically active TRAF6, indicating that it is the physiologically relevant E3. Thus, K63-linked polyubiquitination of proximal signaling proteins is a common mechanism used by diverse innate immune receptors for recruiting IKK and activating NF-kappaB.

Pubmed ID: 18347055 RIS Download

Mesh terms: Animals | Base Sequence | Binding Sites | Cell Line | Cells, Cultured | DNA Primers | Humans | I-kappa B Kinase | Interleukin-1 Receptor-Associated Kinases | Lysine | Mice | NF-kappa B | Receptors, Interleukin-1 | Recombinant Proteins | TNF Receptor-Associated Factor 6 | Toll-Like Receptor 4 | Toll-Like Receptors | Transfection | Ubiquitination

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Associated grants

  • Agency: Intramural NIH HHS, Id:

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