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.
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
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
Mol. Cell. Biol.
Date: May. 01, 2008
PubMed ID: 18347055
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