title: ICEBERG: a novel inhibitor of interleukin-1beta generation.
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.
authors.affiliation: Department of Cellular and Molecular Biology, University of Michigan Medical School, Ann Arbor 48109, USA.
authors.forename: E W
authors.initials: EW
authors.lastname: Humke
authors.forename: S K
authors.initials: SK
authors.lastname: Shriver
authors.forename: M A
authors.initials: MA
authors.lastname: Starovasnik
authors.forename: W J
authors.initials: WJ
authors.lastname: Fairbrother
authors.forename: V M
authors.initials: VM
authors.lastname: Dixit
mesh_terms: D000595:Amino Acid Sequence / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics*; D020170:Caspase 1 / Q000737:chemistry / Q000378:metabolism*; D002478:Cells, Cultured; D018836:Inflammation Mediators / Q000378:metabolism*; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D047908:Intracellular Signaling Peptides and Proteins; D008969:Molecular Sequence Data; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D020539:Sequence Analysis, Protein; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D020931:ran GTP-Binding Protein
chemical_list: C415523:CARD18 protein, human; D002352:Carrier Proteins; D018836:Inflammation Mediators; D007375:Interleukin-1; D047908:Intracellular Signaling Peptides and Proteins; C102460:Ran protein, mouse; D014409:Tumor Necrosis Factor-alpha; D017346:Protein Serine-Threonine Kinases; C506253:RIPK2 protein, human; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506255:Ripk2 protein, mouse; D020170:Caspase 1; D020559:Monomeric GTP-Binding Proteins; D020931:ran GTP-Binding Protein