CIPER, a novel NF κB-activating protein containing a caspase recruitment domain with homology to Herpesvirus-2 protein E10

We have identified and characterized CIPER, a novel protein containing a caspase recruitment domain (CARD) in its N terminus and a C-terminal region rich in serine and threonine residues. The CARD of CIPER showed striking similarity to E10, a product of the equine herpesvirus-a. CIPER formed homodimers via its CARD and interacted with viral E10 but not with several apoptosis regulators containing CARDs including ARC, RAIDD, RICK, caspase-2, caspase-9, or Apaf-1. Expression of CIPER induced NF-kappa B activation, which was inhibited by dominant-negative NIK and a nonphosphorylable I kappa B-alpha mutant but not by dominant-negative RIP. Mutational analysis revealed that the N-terminal region of CIPER containing the CARD was sufficient and necessary for NF-kappa B-inducing activity. Point mutations in highly conserved residues in the CARD of CIPER disrupted the ability of CIPER to activate NF-kappa B and to form homodimers, indicating that the CARD is essential for NF-kappa B activation and dimerization. We propose that CIPER acts in a NIK-dependent pathway of NF-kappa B activation.