Arenavirus nucleoprotein targets interferon regulatory factor-activating kinase IKKepsilon.
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Pythoud C, Rodrigo WW, Pasqual G, Rothenberger S, Martinez-Sobrido L, de la Torre JC, Kunz S
Arenavirus nucleoprotein targets interferon regulatory factor-activating kinase IKKepsilon.
J Virol. 2012 Aug;86(15):7728-38. doi: 10.1128/JVI.00187-12. Epub 2012 Apr 24.
- PubMed ID
- 22532683 [ View in PubMed]
- Abstract
Arenaviruses perturb innate antiviral defense by blocking induction of type I interferon (IFN) production. Accordingly, the arenavirus nucleoprotein (NP) was shown to block activation and nuclear translocation of interferon regulatory factor 3 (IRF3) in response to virus infection. Here, we sought to identify cellular factors involved in innate antiviral signaling targeted by arenavirus NP. Consistent with previous studies, infection with the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) prevented phosphorylation of IRF3 in response to infection with Sendai virus, a strong inducer of the retinoic acid-inducible gene I (RIG-I)/mitochondrial antiviral signaling (MAVS) pathway of innate antiviral signaling. Using a combination of coimmunoprecipitation and confocal microscopy, we found that LCMV NP associates with the IkappaB kinase (IKK)-related kinase IKKepsilon but that, rather unexpectedly, LCMV NP did not bind to the closely related TANK-binding kinase 1 (TBK-1). The NP-IKKepsilon interaction was highly conserved among arenaviruses from different clades. In LCMV-infected cells, IKKepsilon colocalized with NP but not with MAVS located on the outer membrane of mitochondria. LCMV NP bound the kinase domain (KD) of IKKepsilon (IKBKE) and blocked its autocatalytic activity and its ability to phosphorylate IRF3, without undergoing phosphorylation. Together, our data identify IKKepsilon as a novel target of arenavirus NP. Engagement of NP seems to sequester IKKepsilon in an inactive complex. Considering the important functions of IKKepsilon in innate antiviral immunity and other cellular processes, the NP-IKKepsilon interaction likely plays a crucial role in arenavirus-host interaction.