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Review
. 2013 Jun 21;5(6):1587-606.
doi: 10.3390/v5061587.

NF-κB and IRF7 pathway activation by Epstein-Barr virus Latent Membrane Protein 1

Ina Ersing  1 , Katharina Bernhardt, Benjamin E Gewurz
Affiliations
Review

NF-κB and IRF7 pathway activation by Epstein-Barr virus Latent Membrane Protein 1

Ina Ersing et al. Viruses. .

Abstract

The principal Epstein-Barr virus (EBV) oncoprotein, Latent Membrane Protein 1 (LMP1), is expressed in most EBV-associated human malignancies. LMP1 mimics CD40 receptor signaling to provide infected cells with constitutive NF-κB, MAP kinase, IRF7, and PI3 kinase pathway stimulation. EBV-transformed B-cells are particularly dependent on constitutive NF-κB activity, and rapidly undergo apoptosis upon NF-κB blockade. Here, we review LMP1 function, with special attention to current understanding of the molecular mechanisms of LMP1-mediated NF-κB and IRF7 pathway activation. Recent advances include the elucidation of transmembrane motifs important for LMP1 trafficking and ligand-independent signaling, analysis of genome-wide LMP1 gene targets, and the identification of novel cell proteins that mediate LMP1 NF-κB and IRF7 pathway activation.

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Figures

Figure 1
Figure 1
Latent Membrane Protein 1 (LMP1) transmembrane domain residues important for aggregation and signaling. The six LMP1 transmembrane (TM) domains (shown in blue) promote LMP1 multimerization and trafficking to cytoplasmic membrane (shown in green/orange) lipid raft signaling sites. Regions important for LMP1 signaling, aggregation, and trafficking are highlighted.
Figure 2
Figure 2
LMP1-mediated canonical and non-canonical NF-κB pathway activation. Shown are salient events in LMP1 TES1-mediated non-canonical NF-κB pathway activation, and TES2-mediated canonical pathway activation. Kinases are shown in purple, and ubiquitin ligases in blue. In addition, shown on the right, are additional kinases, phosphatases, ubiquitin ligases and deubiquitinating enzyme (DUB) siRNA screen hits that are important for TES2-mediated IκB kinase (IKK) complex activation. See text for full details.
Figure 3
Figure 3
LMP1-mediated IRF7 activation. LMP1 recruits IRF7, promotes its TRAF6-mediated K63-ubiquitination, and C-terminal phosphorylation by as yet unidentified kinase(s). IRF7 translocates to the nucleus to activate target gene transcription, including LMP1 itself. IRF7 transcription is likewise up-regulated by LMP1-mediated NF-κB activation, which creates a positive feedback loop. IRF7 activity is negatively regulated by the DUB A20, and by LMP1-mediated recruitment of the SUMO ligase UBC9. IRF7 SUMOylation impairs its interaction with chromatin.
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