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J. Biol. Chem., Vol. 279, Issue 10, 9642-9652, March 5, 2004

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RICK Activates a NF-B-dependent Anti-human Cytomegalovirus Response^*

Jan Eickhoff, Miriam Hanke, Matthias Stein-Gerlach, Tan Poi Kiang, Katrin Herzberger, Peter Habenberger, Stefan Müller, Bert Klebl, Manfred Marschall, Thomas Stamminger, and Matt Cotten¶

From the Axxima Pharmaceuticals AG, 81377 München, Germany and Institut für Klinische und Molekulare Virologie, Universität Erlangen-Nürnberg, 91054 Erlangen, Germany

The adapter kinase receptor interacting protein-like interacting caspase-like apoptosis regulatory protein kinase (RICK, also called RIP2 and CARDIAK) was found to be elevated at both the protein and RNA levels during human cytomegalovirus (HCMV) replication, suggesting either that the virus may require RICK for replication or that RICK is part of an unsuccessful host attempt to inhibit HCMV replication. It is demonstrated here that forced expression of RICK in either a kinase active or inactive form activates nuclear factor (NF)-B by means of its intermediate domain and potently blocks HCMV replication in human fibroblasts. Importantly, NF-B activation, which exerted a modestly positive effect on the early phase of infection, clearly had a strongly negative impact during later viral steps. A stable inhibitor of NF-B (IB) reverses the RICK inhibitory effect, and activation of NF-B by IB kinase expression is inhibitory to HCMV, demonstrating that NF-B activation is part of a potent anti-HCMV response. Supernatant transfer experiments identified interferon- as a downstream component of the RICK inhibitory pathway. RICK expression was found to synergize with HCMV infection in the induction of interferon- expression. This study identifies an endogenous RICK-activated, NF-B- and interferon--dependent antiviral pathway that is either inhibited or faulty under normal HCMV replication conditions; efforts to bolster this pathway may lead to novel anti-viral approaches.

Received for publication, November 25, 2003

^* This work was supported in part by a grant from the German Bundesministerium für Bildung und Forschung. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Axxima Pharmaceuticals AG, Max-Lebsche-Platz 32, 81377 München, Germany. Tel.: 49-89550-65472; Fax: 49-89550-65461; E-mail: Matt.Cotten{at}axxima.com.

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