A Novel Inhibitor of the NF-κB Signaling Pathway Encoded by the Parapoxvirus Orf Virus

Diel, Diego G.; Delhon, G.; Luo, Shuhong; Flores, Eduardo F.; Rock, Daniel L.

doi:10.1128/jvi.02291-09

Cited by 58 publications

(104 citation statements)

References 67 publications

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“…Thus ORFV024 protein from the parapoxvirus orf virus was shown to block IKK activation although the mechanism of its activity is not clear [34], while two other unique parapoxvirus proteins, ORFV002 and ORFV121, were recently shown to also inhibit NFkB activation. ORFV002 antagonized p65 phosphorylation by interfering with the association of p65 with the mitogen and stress-activated kinase-1 (MSK1) which prevented p65 recruiting the coactivator p300 to NFkB-dependent promoters, thus suppressing transactivation [35].…”

Section: Direct Targeting Of Nfkb and Its Proximal Kinases By Poxvirusesmentioning

confidence: 99%

Innate immune activation of NFκB and its antagonism by poxviruses

Brady

Bowie

2014

Cytokine & Growth Factor Reviews

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Section: Direct Targeting Of Nfkb and Its Proximal Kinases By Poxvirusesmentioning

confidence: 99%

Innate immune activation of NFκB and its antagonism by poxviruses

Brady

Bowie

2014

Cytokine & Growth Factor Reviews

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“…HeLa cells stably expressing green fluorescent protein (GFP) (GFP/HeLa) or ORFV121-GFP (121GFP/ HeLa) fusion protein were established as previously described (11) and maintained in Dulbecco's modified essential medium (DMEM) supplemented with 10% FBS, 2 mM L-glutamine, gentamicin (50 g/ml), penicillin (100 g/ml), streptomycin (100 g/ml), and neomycin (G418; 500 g/ml; Gibco). ORFV strain OV-IA82 (10) was used to construct an ORFV121 deletion mutant virus (OV-IA82⌬121) in all procedures involving wild-type virus infection and in the cloning of viral genes.…”

Section: Cells and Virusesmentioning

confidence: 99%

“…Cells were inoculated with OV-IA82 (multiplicity of infection [MOI], 10) in the presence or absence of cytosine arabinoside (AraC; 40 g/ml) and harvested at 0, 1, 2, 3, 6, 12, and 24 h postinoculation (p.i.). RNA samples were processed and reverse transcribed as previously described (11). The transcription of ORFV121, ORFV024 (early control gene), and ORFV059 (late control gene) was assessed by PCR using primers 121Fw (5Ј-TCCAGCTGCCCGCGACGACGCGC-3Ј), 121Rv (5Ј-GGAGGTTGGGTCTGCCGGCGCCGCA-3Ј), 024Fw (5Ј-GCGGA CACAGCCACAACCACAGTC-3Ј), 024Rv (5Ј-CTAGCACGCGCTTTCGGT ACCGCC-3Ј), 059Fw (5Ј-ATGGATCCACCCGAAATCAC-3Ј), and 059Rv (5Ј-TCACACGATGGCCGTGACCAGC-3Ј), respectively.…”

Section: Cells and Virusesmentioning

confidence: 99%

“…ORFV121 deletion mutant OV-IA82⌬121 virus was generated by homologous recombination between OV-IA82 and the recombination vector pZippy-121LF-Neo/Gus-121RF (11). The absence of ORFV121 sequence and the presence of Neo/Gus sequences in the purified recombinant virus were determined by PCR and Southern blotting.…”

Section: Cells and Virusesmentioning

confidence: 99%

“…Recently, two novel inhibitors of NF-B have been identified in the parapoxvirus ORFV, ORFV024 and ORFV002 (11,12). ORFV024 was shown to inhibit the phosphorylation of IB kinases, thus preventing the activation of the IKK complex (11), while ORFV002 encodes a nuclear NF-B inhibitor that prevents the p300-mediated acetylation of the transactivating NF-B subunit NF-B-p65 (12).…”

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confidence: 99%

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Orf Virus ORFV121 Encodes a Novel Inhibitor of NF-κB That Contributes to Virus Virulence

Diel

Luo

Delhon

et al. 2011

J Virol

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Orf virus (ORFV), the type member of the genus Parapoxvirus of the Poxviridae, has evolved novel strategies (proteins and/or mechanisms of action) to modulate host cell responses regulated by the nuclear factor-B (NF-B) signaling pathway. Here, we present data indicating that ORFV ORFV121, a gene unique to parapoxviruses, encodes a novel viral NF-B inhibitor that binds to and inhibits the phosphorylation and nuclear translocation of NF-B-p65. The infection of cells with an ORFV121 deletion mutant virus (OV-IA82⌬121) resulted in increased NF-B-mediated gene transcription, and the expression of ORFV121 in cell cultures significantly suppressed NF-B-regulated reporter gene expression. ORFV ORFV121 physically interacts with NF-B-p65 in the cell cytoplasm, thus providing a mechanism for the inhibition of NF-B-p65 phosphorylation and nuclear translocation. Notably, the deletion of ORFV121 from the viral genome markedly decreased ORFV virulence and disease pathogenesis in sheep, indicating that ORFV121 is a virulence determinant for ORFV in the natural host.

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Total chemical synthesis of an Orf virus protein, ORFV002, an inhibitor of the master gene regulator NF‐κB

et al. 2014

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ORFV002 is a novel orf viral protein (117 Aa) that inhibits nuclear events through the regulation of the transcriptional activity of NF-κB, a master regulator of human gene expression (Diel et al., J Virol 2011, 85, 264-275). It is identified as the first nuclear inhibitor of NF-κB produced by orf virus (ORFV) and no homologues in other genera of the Chordopoxvirinae subfamily have been reported to date (Diel et al., J Virol 2011, 85, 264-275). Our molecular structure predictions suggest that ORFV002 may mimic part of IκB, an inhibitor and natural human partner of NF-κB. Recent advances in total chemical synthesis of proteins have provided solutions in overcoming challenges of current recombinant methods of protein isolation for structure elucidation. Aided by Boc solid phase peptide synthesis and native chemical ligation, ORFV002 was successfully synthesized in multimilligram amounts in good yield and high purity.

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A Novel Inhibitor of the NF-κB Signaling Pathway Encoded by the Parapoxvirus Orf Virus

Cited by 58 publications

References 67 publications

Innate immune activation of NFκB and its antagonism by poxviruses

Innate immune activation of NFκB and its antagonism by poxviruses

Orf Virus ORFV121 Encodes a Novel Inhibitor of NF-κB That Contributes to Virus Virulence

Total chemical synthesis of an Orf virus protein, ORFV002, an inhibitor of the master gene regulator NF‐κB

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