PMID:12829834

Citation	Basler, CF, Mikulasova, A, Martinez-Sobrido, L, Paragas, J, Mühlberger, E, Bray, M, Klenk, HD, Palese, P and García-Sastre, A (2003) The Ebola virus VP35 protein inhibits activation of interferon regulatory factor 3. J. Virol. 77:7945-56
Abstract	The Ebola virus VP35 protein was previously found to act as an interferon (IFN) antagonist which could complement growth of influenza delNS1 virus, a mutant influenza virus lacking the influenza virus IFN antagonist protein, NS1. The Ebola virus VP35 could also prevent the virus- or double-stranded RNA-mediated transcriptional activation of both the beta IFN (IFN-beta) promoter and the IFN-stimulated ISG54 promoter (C. Basler et al., Proc. Natl. Acad. Sci. USA 97:12289-12294, 2000). We now show that VP35 inhibits virus infection-induced transcriptional activation of IFN regulatory factor 3 (IRF-3)-responsive mammalian promoters and that VP35 does not block signaling from the IFN-alpha/beta receptor. The ability of VP35 to inhibit this virus-induced transcription correlates with its ability to block activation of IRF-3, a cellular transcription factor of central importance in initiating the host cell IFN response. We demonstrate that VP35 blocks the Sendai virus-induced activation of two promoters which can be directly activated by IRF-3, namely, the ISG54 promoter and the ISG56 promoter. Further, expression of VP35 prevents the IRF-3-dependent activation of the IFN-alpha4 promoter in response to viral infection. The inhibition of IRF-3 appears to occur through an inhibition of IRF-3 phosphorylation. VP35 blocks virus-induced IRF-3 phosphorylation and subsequent IRF-3 dimerization and nuclear translocation. Consistent with these observations, Ebola virus infection of Vero cells activated neither transcription from the ISG54 promoter nor nuclear accumulation of IRF-3. These data suggest that in Ebola virus-infected cells, VP35 inhibits the induction of antiviral genes, including the IFN-beta gene, by blocking IRF-3 activation.
Links	PubMed PMC161945
Keywords	Animals; Cell Line; Cell Nucleus/metabolism; Cercopithecus aethiops; DNA-Binding Proteins/metabolism; Ebolavirus/metabolism; Ebolavirus/pathogenicity; Humans; Interferon Regulatory Factor-3; Interferon-alpha/metabolism; Interferon-beta/metabolism; Nucleoproteins/physiology; Phosphorylation; Sendai virus/pathogenicity; Transcription Factors/metabolism; Transcriptional Activation; Transfection; Vero Cells; Viral Core Proteins/physiology
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
EBOZM:VP35		GO:0039613: suppression by virus of host protein phosphorylation	ECO:0000314:		P		Figure 4 shows VP35 blocks dimerization and phosphorylation of IRF-3 in response to SeV infection.	complete CACAO 5213
EBOZM:VP35		GO:0010629: negative regulation of gene expression	ECO:0000314:		P		Figure 2:The Ebola virus VP35 protein can block virus-induced, IRF-3-dependent gene expression.	complete CACAO 5359
EBOZM:VP35		GO:0046983: protein dimerization activity	ECO:0000314:		F		Figure 4: VP35 blocks dimerization	complete CACAO 5360
EBOZM:VP35	involved_in	GO:0010629: negative regulation of gene expression	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete

References

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