PMID:15919920

Citation	Brzózka, K, Finke, S and Conzelmann, KK (2005) Identification of the rabies virus alpha/beta interferon antagonist: phosphoprotein P interferes with phosphorylation of interferon regulatory factor 3. J. Virol. 79:7673-81
Abstract	Rabies virus (RV) of the Rhabdoviridae family grows in alpha/beta interferon (IFN)-competent cells, suggesting the existence of viral mechanisms preventing IFN gene expression. We here identify the viral phosphoprotein P as the responsible IFN antagonist. The critical involvement of P was first suggested by the observation that an RV expressing an enhanced green fluorescent protein (eGFP)-P fusion protein (SAD eGFP-P) (S. Finke, K. Brzozka, and K. K. Conzelmann, J. Virol. 78:12333-12343, 2004) was eliminated in IFN-competent HEp-2 cell cultures, in contrast to wild-type (wt) RV or an RV replicon lacking the genes for matrix protein and glycoprotein. SAD eGFP-P induced transcription of the IFN-beta gene and expression of the IFN-responsive MxA and STAT-1 genes. Similarly, an RV expressing low levels of P, which was generated by moving the P gene to a promoter-distal gene position (SAD DeltaPLP), lost the ability to prevent IFN induction. The analysis of RV mutants lacking expression of truncated P proteins P2, P3, or P4, which are expressed from internal AUG codons of the wt RV P open reading frame, further showed that full-length P is competent in suppressing IFN-beta gene expression. In contrast to wt RV, the IFN-inducing SAD DeltaPLP caused S386 phosphorylation, dimerization, and transcriptional activity of IFN regulatory factor 3 (IRF-3). Phosphorylation of IRF-3 by TANK-binding kinase-1 expressed from transfected plasmids was abolished in wt RV-infected cells or by cotransfection of P-encoding plasmids. Thus, RV P is necessary and sufficient to prevent a critical IFN response in virus-infected cells by targeting activation of IRF-3 by an upstream kinase.
Links	PubMed PMC1143667 Online version:10.1128/JVI.79.12.7673-7681.2005
Keywords	Animals; Cell Line; Cercopithecus aethiops; DNA-Binding Proteins/metabolism; Green Fluorescent Proteins/genetics; Green Fluorescent Proteins/metabolism; Humans; Interferon Regulatory Factor-3; Interferon-alpha/antagonists & inhibitors; Interferon-alpha/metabolism; Interferon-beta/antagonists & inhibitors; Interferon-beta/metabolism; Phosphoproteins/genetics; Phosphoproteins/metabolism; Phosphorylation; Protein-Serine-Threonine Kinases/metabolism; Rabies virus/genetics; Rabies virus/metabolism; Rabies virus/pathogenicity; Recombinant Fusion Proteins/genetics; Recombinant Fusion Proteins/metabolism; Transcription Factors/metabolism; Transcriptional Activation/drug effects; Vero Cells; Viral Structural Proteins/genetics; Viral Structural Proteins/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
RABVS:PHOSP		GO:0039653: suppression by virus of host transcription	ECO:0000315:		P		Figure 6. Expression of P is sufficient to prevent TBK-1-mediated IFN-β induction.	complete CACAO 9072
RABVS:PHOSP	involved_in	GO:0039653: suppression by virus of host transcription	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete

References

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