The kinase IKKα inhibits activation of the transcription factor NF-κB by phosphorylating the regulatory molecule TAX1BP1

Nat Immunol. 2011 Jul 17;12(9):834-43. doi: 10.1038/ni.2066.

Abstract

In response to stimulation with proinflammatory cytokines, the deubiquitinase A20 inducibly interacts with the regulatory molecules TAX1BP1, Itch and RNF11 to form the A20 ubiquitin-editing complex. However, the molecular signal that coordinates the assembly of this complex has remained elusive. Here we demonstrate that TAX1BP1 was inducibly phosphorylated on Ser593 and Ser624 in response to proinflammatory stimuli. The kinase IKKα, but not IKKβ, was required for phosphorylation of TAX1BP1 and directly phosphorylated TAX1BP1 in response to stimulation with tumor necrosis factor (TNF) or interleukin 1 (IL-1). TAX1BP1 phosphorylation was pivotal for cytokine-dependent interactions among TAX1BP1, A20, Itch and RNF11 and downregulation of signaling by the transcription factor NF-κB. IKKα therefore serves a key role in the negative feedback of NF-κB canonical signaling by orchestrating assembly of the A20 ubiquitin-editing complex to limit inflammatory gene activation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibodies, Phospho-Specific / immunology
  • Antibodies, Phospho-Specific / pharmacology
  • Carrier Proteins / genetics
  • Carrier Proteins / immunology*
  • Carrier Proteins / metabolism
  • Cell Line
  • Cloning, Molecular
  • Cysteine Endopeptidases / genetics
  • Cysteine Endopeptidases / immunology*
  • Cysteine Endopeptidases / metabolism
  • DNA-Binding Proteins
  • Escherichia coli
  • Fibroblasts / drug effects
  • Fibroblasts / immunology
  • Gene Deletion
  • Gene Expression Regulation
  • Humans
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / immunology*
  • I-kappa B Kinase / metabolism
  • I-kappa B Kinase / pharmacology
  • Immunity, Innate*
  • Interleukin-1 / immunology
  • Interleukin-1 / pharmacology
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / immunology*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mice
  • NF-kappa B / genetics
  • NF-kappa B / immunology*
  • NF-kappa B / metabolism
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / immunology*
  • Neoplasm Proteins / metabolism
  • Phosphorylation / drug effects*
  • Recombinant Proteins / genetics
  • Recombinant Proteins / immunology*
  • Recombinant Proteins / metabolism
  • Signal Transduction
  • Tumor Necrosis Factor alpha-Induced Protein 3
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor Necrosis Factor-alpha / pharmacology
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / immunology*
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination / drug effects

Substances

  • Antibodies, Phospho-Specific
  • Carrier Proteins
  • DNA-Binding Proteins
  • Interleukin-1
  • Intracellular Signaling Peptides and Proteins
  • NF-kappa B
  • Neoplasm Proteins
  • RNF11 protein, human
  • Recombinant Proteins
  • TAX1BP1 protein, mouse
  • Tumor Necrosis Factor-alpha
  • Itch protein, mouse
  • Ubiquitin-Protein Ligases
  • I-kappa B Kinase
  • Tumor Necrosis Factor alpha-Induced Protein 3
  • Cysteine Endopeptidases
  • Tnfaip3 protein, mouse