CLAP, a novel caspase recruitment domain-containing protein in the tumor necrosis factor receptor pathway, regulates NF-kappa B activation and apoptosis

Molecules that regulate NF-kappa B activation play critical roles in apopto sis and inflammation. We describe the cloning of the cellular homolog of th e equine herpesvirus-2 protein E10 and show that both proteins regulate apo ptosis and NF-kappa B activation. These proteins were found to contain N-te rminal caspase-recruitment domains (CARDs) and novel C-terminal domains (CT Ds) and were therefore named CLAPs (CARD-like apoptotic proteins). The cell ular and viral CLAPs induce apoptosis downstream of caspase-8 by activating the Apaf-1-caspase-9 pathway and activate NF-kappa B by acting upstream of the NF-kappa B-inducing kinase, NIK, and the IkB kinase, IKK alpha. Deleti on of either the CARD or the CTD domain inhibits both activities, The CARD domain was found to be important for homo- and heterodimerization of CLAPs, Substitution of the CARD domain with an inducible FKBP12 oligomerization d omain produced a molecule that can induce NF-kappa B activation, suggesting that the CARD domain functions as an oligomerization domain, whereas the C TD domain functions as the effector domain in the NF-kappa B activation pat hway. Expression of the CARD domain of human CLAP abrogates tumor necrosis factor-cw-induced NF-kappa B activation, suggesting that cellular CLAP play s an essential role in this pathway of NF-kappa B activation.