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 journalArticle

151 Citations (Scopus)

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

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Interleukin-1 Receptors
Toll-Like Receptors
Ubiquitination
TNF Receptor-Associated Factor 6
Polyubiquitin
Mitogen-Activated Protein Kinases
Interleukin-1
Arginine
Phosphotransferases
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Lys63-linked polyubiquitination of IRAK-1 is required for interleukin-1 receptor- and toll-like receptor-mediated NF-κB activation. / Conze, Dietrich B.; Wu, Chuan Jin; Thomas, James A.; Landstrom, Allison; Ashwell, Jonathan D.

In: Molecular and Cellular Biology, Vol. 28, No. 10, 05.2008, p. 3538-3547.

Research output: Contribution to journalArticle

Conze, Dietrich B. ; Wu, Chuan Jin ; Thomas, James A. ; Landstrom, Allison ; Ashwell, Jonathan D. / Lys63-linked polyubiquitination of IRAK-1 is required for interleukin-1 receptor- and toll-like receptor-mediated NF-κB activation. In: Molecular and Cellular Biology. 2008 ; Vol. 28, No. 10. pp. 3538-3547.
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