Tumor necrosis factor alpha induction of NF-kappaB requires the novel coactivator SIMPL

Mol Cell Biol. 2004 Nov;24(21):9317-26. doi: 10.1128/MCB.24.21.9317-9326.2004.

Abstract

A myriad of stimuli including proinflammatory cytokines, viruses, and chemical and mechanical insults activate a kinase complex composed of IkappaB kinase beta (IKK-beta), IKK-alpha, and IKK-gamma/N, leading to changes in NF-kappaB-dependent gene expression. However, it is not clear how the NF-kappaB response is tailored to specific cellular insults. Signaling molecule that interacts with mouse pelle-like kinase (SIMPL) is a signaling component required for tumor necrosis factor alpha (TNF-alpha)-dependent but not interleukin-1-dependent NF-kappaB activation. Herein we demonstrate that nuclear localization of SIMPL is required for type I TNF receptor-induced NF-kappaB activity. SIMPL interacts with nuclear p65 in a TNF-alpha-dependent manner to promote endogenous NF-kappaB-dependent gene expression. The interaction between SIMPL and p65 enhances p65 transactivation activity. These data support a model in which TNF-alpha activation of NF-kappaB dependent-gene expression requires nuclear relocalization of p65 as well as nuclear relocalization of SIMPL, generating a TNF-alpha-specific induction of gene expression.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • CCAAT-Enhancer-Binding Proteins / genetics
  • CCAAT-Enhancer-Binding Proteins / metabolism
  • Carrier Proteins / chemistry
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Line
  • Cell Nucleus / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Molecular Sequence Data
  • Multiprotein Complexes
  • NF-kappa B / agonists
  • NF-kappa B / chemistry
  • NF-kappa B / metabolism*
  • Nuclear Localization Signals / chemistry
  • Protein Structure, Tertiary
  • Protein Transport
  • Proto-Oncogene Proteins c-jun / genetics
  • Proto-Oncogene Proteins c-jun / metabolism
  • Receptors, Tumor Necrosis Factor, Type I / metabolism
  • Transcription Factor RelA
  • Transcriptional Activation
  • Tumor Necrosis Factor-alpha / pharmacology*

Substances

  • CCAAT-Enhancer-Binding Proteins
  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • Multiprotein Complexes
  • NF-kappa B
  • Nuclear Localization Signals
  • Proto-Oncogene Proteins c-jun
  • Receptors, Tumor Necrosis Factor, Type I
  • SIMPL protein, mouse
  • Transcription Factor RelA
  • Tumor Necrosis Factor-alpha