The zinc finger protein A20 inhibits TNF-induced NF-kappaB-dependent gene expression by interfering with an RIP- or TRAF2-mediated transactivation signal and directly binds to a novel NF-kappaB-inhibiting protein ABIN

J Cell Biol. 1999 Jun 28;145(7):1471-82. doi: 10.1083/jcb.145.7.1471.

Abstract

The zinc finger protein A20 is a tumor necrosis factor (TNF)- and interleukin 1 (IL-1)-inducible protein that negatively regulates nuclear factor-kappa B (NF-kappaB)-dependent gene expression. However, the molecular mechanism by which A20 exerts this effect is still unclear. We show that A20 does not inhibit TNF- induced nuclear translocation and DNA binding of NF-kappaB, although it completely prevents the TNF- induced activation of an NF-kappaB-dependent reporter gene, as well as TNF-induced IL-6 and granulocyte macrophage-colony stimulating factor gene expression. Moreover, NF-kappaB activation induced by overexpression of the TNF receptor-associated proteins TNF receptor-associated death domain protein (TRADD), receptor interacting protein (RIP), and TNF recep- tor-associated factor 2 (TRAF2) was also inhibited by expression of A20, whereas NF-kappaB activation induced by overexpression of NF-kappaB-inducing kinase (NIK) or the human T cell leukemia virus type 1 (HTLV-1) Tax was unaffected. These results demonstrate that A20 inhibits NF-kappaB-dependent gene expression by interfering with a novel TNF-induced and RIP- or TRAF2-mediated pathway that is different from the NIK-IkappaB kinase pathway and that is specifically involved in the transactivation of NF-kappaB. Via yeast two-hybrid screening, we found that A20 binds to a novel protein, ABIN, which mimics the NF-kappaB inhibiting effects of A20 upon overexpression, suggesting that the effect of A20 is mediated by its interaction with this NF-kappaB inhibiting protein, ABIN.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Line
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cysteine Endopeptidases
  • DNA / genetics
  • DNA / metabolism
  • DNA-Binding Proteins
  • Enzyme Activation / drug effects
  • Gene Products, tax / genetics
  • Gene Products, tax / metabolism
  • Granulocyte-Macrophage Colony-Stimulating Factor / genetics
  • Humans
  • Interleukin-6 / genetics
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Mitogen-Activated Protein Kinases*
  • Molecular Sequence Data
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / physiology
  • Protein Binding / drug effects
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Proteins / chemistry
  • Proteins / genetics
  • Proteins / metabolism*
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Signal Transduction / drug effects
  • TNF Receptor-Associated Death Domain Protein
  • TNF Receptor-Associated Factor 1
  • TNF Receptor-Associated Factor 2
  • Trans-Activators / genetics
  • Trans-Activators / physiology
  • Transcriptional Activation* / drug effects
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins*
  • Tumor Necrosis Factor alpha-Induced Protein 3
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • Tumor Necrosis Factor-alpha / pharmacology
  • Yeasts / genetics
  • Zinc Fingers
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Carrier Proteins
  • DNA-Binding Proteins
  • Gene Products, tax
  • Interleukin-6
  • Intracellular Signaling Peptides and Proteins
  • NF-kappa B
  • Nuclear Proteins
  • Proteins
  • TNF Receptor-Associated Death Domain Protein
  • TNF Receptor-Associated Factor 1
  • TNF Receptor-Associated Factor 2
  • Tradd protein, mouse
  • Trans-Activators
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
  • Tumor Necrosis Factor-alpha
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • DNA
  • Protein-Serine-Threonine Kinases
  • RIPK1 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk1 protein, mouse
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • NF-kappa B kinase
  • TNFAIP3 protein, human
  • Tumor Necrosis Factor alpha-Induced Protein 3
  • Cysteine Endopeptidases
  • Tnfaip3 protein, mouse

Associated data

  • GENBANK/AJ242777
  • GENBANK/AJ242778