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

Dietrich B. Conze, Chuan Jin Wu, James A. Thomas, Allison Landstrom, Jonathan D. Ashwell

Research output: Contribution to journalArticlepeer-review

156 Scopus citations

Abstract

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-κB 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 IκB 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-κB 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-κB.

Original languageEnglish (US)
Pages (from-to)3538-3547
Number of pages10
JournalMolecular and cellular biology
Volume28
Issue number10
DOIs
StatePublished - May 2008

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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