RICK activates a NF-kappaB-dependent anti-human cytomegalovirus response.
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.
Eickhoff
Jan
J
Axxima Pharmaceuticals AG, 81377 München, Germany.
Hanke
Miriam
M
Stein-Gerlach
Matthias
M
Kiang
Tan Poi
TP
Herzberger
Katrin
K
Habenberger
Peter
P
Müller
Stefan
S
Klebl
Bert
B
Marschall
Manfred
M
Stamminger
Thomas
T
Cotten
Matt
M
D002460:Cell Line; D003587:Cytomegalovirus / Q000502:physiology*; D003586:Cytomegalovirus Infections / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism / Q000821:virology; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D014779:Virus Replication
D016328:NF-kappa B; D011494:Protein Kinases; C506253:RIPK2 protein, human; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2