Abstract

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

Highlights

  • The Rel/nuclear factor ␬B (NF-␬B) family of transcriptional factors plays an important role in immune and inflammatory responses, cell survival, and stress response by regulating the expression of numerous cellular and viral genes [1]

  • Structural and functional analyses of tumor necrosis factor receptor (TNFR) family members and interleukin-1/Toll receptors have revealed the existence of common intracellular mechanisms that are responsible for signal transduction and biological activities

  • Several TNFR-associated factors (TRAFs) directly interact with the cytoplasmic domain of TNFR family members, whereas these adaptor molecules associate with TNFR1 via the adaptor molecule TRADD and the Ser/Thr kinase RIP [12]

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Summary

Introduction

The Rel/NF-␬B family of transcriptional factors plays an important role in immune and inflammatory responses, cell survival, and stress response by regulating the expression of numerous cellular and viral genes [1]. Novel CARD-containing Protein CIPER Induces NF-␬B Activation recruitment of this caspase to the TNFR1 complex [15]. To identify novel regulators of intracellular pathways, we searched public data bases for expressed sequence tag (EST) clones with homology to the CARD of caspase-2.

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