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

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.

Pubmed ID: 21765415

Authors

  • Shembade N
  • Pujari R
  • Harhaj NS
  • Abbott DW
  • Harhaj EW

Journal

Nature immunology

Publication Data

September 19, 2011

Associated Grants

  • Agency: NIDDK NIH HHS, Id: P01 DK091222
  • Agency: NIGMS NIH HHS, Id: R01 GM083143
  • Agency: NIGMS NIH HHS, Id: R01 GM086550
  • Agency: NIGMS NIH HHS, Id: R01 GM086550-03
  • Agency: NCI NIH HHS, Id: R01CA135362
  • Agency: NIGMS NIH HHS, Id: R01GM083143
  • Agency: NIAID NIH HHS, Id: R21 AI091637
  • Agency: NIAID NIH HHS, Id: R21 AI091637-01A1

Mesh Terms

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