β-TrCP-mediated IRAK1 degradation releases TAK1-TRAF6 from the membrane to the cytosol for TAK1-dependent NF-κB activation

Mol Cell Biol. 2012 Oct;32(19):3990-4000. doi: 10.1128/MCB.00722-12. Epub 2012 Jul 30.

Abstract

Interleukin-1 (IL-1) receptor-associated kinase (IRAK1) is phosphorylated, ubiquitinated, and degraded upon IL-1 stimulation. IRAK1 can be ubiquitinated through both K48- and K63-linked polyubiquitin chains upon IL-1 stimulation. While the Pellino proteins have been shown to meditate K63-linked polyubiquitination on IRAK1, the E3 ligase for K48-linked ubiquitination of IRAK1 has not been identified. In this study, we report that the SCF (Skp1-Cullin1-F-box)-β-TrCP complex functions as the K48-linked ubiquitination E3 ligase for IRAK1. IL-1 stimulation induced the interaction of IRAK1 with Cullin1 and β-TrCP. Knockdown of β-TrCP1 and β-TrCP2 attenuated the K48-linked ubiquitination and degradation of IRAK1. Importantly, β-TrCP deficiency abolished the translocation TAK1-TRAF6 complex from the membrane to the cytosol, resulting in a diminishment of the IL-1-induced TAK1-dependent pathway. Taken together, these results implicate a positive role of β-TrCP-mediated IRAK1 degradation in IL-1-induced TAK1 activation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Cytosol
  • Gene Knockdown Techniques
  • Humans
  • I-kappa B Kinase / immunology
  • I-kappa B Kinase / metabolism
  • Interleukin-1 / immunology*
  • Interleukin-1 Receptor-Associated Kinases / immunology*
  • Interleukin-1 Receptor-Associated Kinases / metabolism
  • MAP Kinase Kinase 4 / immunology
  • MAP Kinase Kinase 4 / metabolism
  • MAP Kinase Kinase Kinases / immunology*
  • MAP Kinase Kinase Kinases / metabolism
  • NF-kappa B / immunology*
  • Phosphorylation
  • Protein Transport
  • TNF Receptor-Associated Factor 6 / immunology*
  • TNF Receptor-Associated Factor 6 / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / immunology*
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination
  • beta-Transducin Repeat-Containing Proteins / genetics
  • beta-Transducin Repeat-Containing Proteins / immunology*
  • beta-Transducin Repeat-Containing Proteins / metabolism

Substances

  • BTRC protein, human
  • FBXW11 protein, human
  • Interleukin-1
  • NF-kappa B
  • TNF Receptor-Associated Factor 6
  • beta-Transducin Repeat-Containing Proteins
  • Ubiquitin-Protein Ligases
  • IRAK1 protein, human
  • Interleukin-1 Receptor-Associated Kinases
  • I-kappa B Kinase
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • MAP Kinase Kinase 4