ICEBERG: a novel inhibitor of interleukin-1beta generation

Cell. 2000 Sep 29;103(1):99-111. doi: 10.1016/s0092-8674(00)00108-2.

Abstract

ProIL-1beta is a proinflammatory cytokine that is proteolytically processed to its active form by caspase-1. Upon receipt of a proinflammatory stimulus, an upstream adaptor, RIP2, binds and oligomerizes caspase-1 zymogen, promoting its autoactivation. ICEBERG is a novel protein that inhibits generation of IL-1beta by interacting with caspase-1 and preventing its association with RIP2. ICEBERG is induced by proinflammatory stimuli, suggesting that it may be part of a negative feedback loop. Consistent with this, enforced retroviral expression of ICEBERG inhibits lipopolysaccharide-induced IL-1beta generation. The structure of ICEBERG reveals it to be a member of the death-domain-fold superfamily. The distribution of surface charge is complementary to the homologous prodomain of caspase-1, suggesting that charge-charge interactions mediate binding of ICEBERG to the prodomain of caspase-1.

Publication types

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

MeSH terms

  • Amino Acid Sequence / physiology*
  • Carrier Proteins / genetics*
  • Caspase 1 / chemistry
  • Caspase 1 / metabolism*
  • Cells, Cultured
  • Inflammation Mediators / metabolism*
  • Interleukin-1 / antagonists & inhibitors*
  • Interleukin-1 / biosynthesis*
  • Intracellular Signaling Peptides and Proteins*
  • Molecular Sequence Data
  • Monomeric GTP-Binding Proteins / metabolism
  • Monomeric GTP-Binding Proteins / pharmacology
  • Protein Serine-Threonine Kinases / chemistry
  • Protein Serine-Threonine Kinases / metabolism*
  • Receptor-Interacting Protein Serine-Threonine Kinase 2
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Sequence Analysis, Protein
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology
  • ran GTP-Binding Protein

Substances

  • CARD18 protein, human
  • Carrier Proteins
  • Inflammation Mediators
  • Interleukin-1
  • Intracellular Signaling Peptides and Proteins
  • Ran protein, mouse
  • Tumor Necrosis Factor-alpha
  • Protein Serine-Threonine Kinases
  • RIPK2 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinase 2
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk2 protein, mouse
  • Caspase 1
  • Monomeric GTP-Binding Proteins
  • ran GTP-Binding Protein

Associated data

  • GENBANK/AF208005
  • PDB/1DGN