RICK activates a NF-kappaB-dependent anti-human cytomegalovirus response.

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

doi:10.1074/jbc.m312893200

Jan Eickhoff, Tan Poi Kiang + Show 9 more

Open Access

https://doi.org/10.1074/jbc.m312893200

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Abstract

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)-kappaB by means of its intermediate domain and potently blocks HCMV replication in human fibroblasts. Importantly, NF-kappaB 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-kappaB (IkappaB) reverses the RICK inhibitory effect, and activation of NF-kappaB by IkappaB kinase beta expression is inhibitory to HCMV, demonstrating that NF-kappaB activation is part of a potent anti-HCMV response. Supernatant transfer experiments identified interferon-beta as a downstream component of the RICK inhibitory pathway. RICK expression was found to synergize with HCMV infection in the induction of interferon-beta expression. This study identifies an endogenous RICK-activated, NF-kappaB- and interferon-beta-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.

Highlights

Alterations in host gene expression can be a useful starting point in efforts to identify novel anti-viral strategies
RICK mRNA and Protein Levels Are Increased during human cytomegalovirus (HCMV) Infection—In a broad screen of cellular signaling molecules influenced by HCMV replication, the serine/threonine adapter kinase RICK was found to be up-regulated during productive HCMV replication in primary human foreskin fibroblasts (HFFs)
We clearly demonstrate that expression of RICK leads to the inhibition of HCMV replication

Summary

Introduction

Alterations in host gene expression can be a useful starting point in efforts to identify novel anti-viral strategies. Studies with mice homozygous for a disrupted RICK allele demonstrate an essential role for RICK in activating NF-␬B, p38, c-Jun NH2-terminal kinase, and extracellular signal-regulated kinase downstream of several toll-like receptors and the intracellular NOD1 and NOD2 molecules, as well as playing an important role in the activation of interferon-␥ expression in response to a variety of stimuli [9, 15] Given this broad range of cellular events activated by RICK, we sought to determine whether the observed RICK up-regulation is stimulatory to HCMV replication or, alternately, is activated by the host in response to HCMV infection and is part of a host defense program. It seems that RICK is contributing to the innate immune response of the HCMV infection, a response that under normal conditions is not sufficient to prevent HCMV replication

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