COP, a Caspase Recruitment Domain-containing Protein and Inhibitor of Caspase-1 Activation Processing

The production of bio-active interleukin-1β (IL-1β), a pro-inflammatory cytokine, is mediated by activated caspase-1. One of the known molecular mechanisms underlying pro-caspase-1 processing and activation involves binding of the caspase-1 prodomain to a caspase recruitment domain (CARD)-containing serine/threonine kinase known as RIP2/CARDIAK/RICK. We have identified a novel protein, COP (CARD only protein), which has a high degree of sequence identity to the caspase-1 prodomain. COP binds to both RIP2 and the caspase-1 prodomain and inhibits RIP2-induced caspase-1 oligomerization. COP inhibits caspase-1-induced IL-1β secretion as well as lipopolysaccharide-induced IL-1β secretion in transfected cells. Our data indicate that COP can regulate IL-1β secretion, implying that COP may play a role in down-regulating inflammatory responses analogous to the CARD protein ICEBERG.