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-2. 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-κB activation, which was inhibited by dominant-negative NIK and a nonphosphorylable IκB-α 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-κB-inducing activity. Point mutations in highly conserved residues in the CARD of CIPER disrupted the ability of CIPER to activate NF-κB and to form homodimers, indicating that the CARD is essential for NF-κB activation and dimerization. We propose that CIPER acts in a NIK-dependent pathway of NF- κB activation.
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