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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


  • Conze DB
  • Wu CJ
  • Thomas JA
  • Landstrom A
  • Ashwell JD


Molecular and cellular biology

Publication Data

May 29, 2008

Associated Grants

  • Agency: Intramural NIH HHS, Id:

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