ICEBERG: A novel inhibitor of interleukin-1 beta generation

ProIL-1 beta is a proinflammatory cytokine that is proteolytically processe d to its active form by caspase-1. Upon receipt of a proinflammatory stimul us, an upstream adaptor, RIP2, binds and oligomerizes caspase-1 zymogen, pr omoting its autoactivation. ICEBERG is a novel protein that inhibits genera tion of IL-1 beta by interacting with caspase-1 and preventing its associat ion with RIP2. ICEBERG is induced by proinflammatory stimuli, suggesting th at it may be part of a negative feedback loop. Consistent with this, enforc ed retroviral expression of ICEBERG inhibits lipopolysaccharide-induced IL- 1 beta generation. The structure of ICEBERG reveals it to be a member of th e death-domain-fold superfamily. The distribution of surface charge is comp lementary to the homologous prodomain of caspase-1, suggesting that charge- charge interactions mediate binding of ICEBERG to the prodomain of caspase- 1.