A Nuclear Inhibitor of NF-κB Encoded by a Poxvirus

Diel, Diego G.; Luo, Shuhong; Delhon, G.; Peng, Yongzheng; Flores, Eduardo Furtado; Rock, Daniel L.

doi:10.1128/jvi.01149-10

Cited by 53 publications

(90 citation statements)

References 46 publications

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“…Histological changes and inflammatory responses induced by OV-IA82⌬121 were less severe than those induced by the wild-type or revertant viruses. These results contrast with our findings for ORFV-encoded NF-B inhibitors ORFV002 and ORFV024, where viruses containing individual gene deletions had no significant effect on ORFV virulence and disease pathogenesis in sheep (11,12). These observations suggest that, in addition to possible complementary functions, individual NF-B inhibitors encoded by ORFV modulate distinct cellular processes regulated by the NF-B signaling pathway during infection in vivo (e.g., immune responses, cell proliferation, cell differentiation, and/or apoptosis).…”

Section: Discussioncontrasting

confidence: 57%

“…ORFV infection markedly suppresses NF-B-mediated transcription in primary OFTu cells (11,12), indicating that this virus efficiently blocks the activation of the NF-B signaling pathway. Here, the novel ORFV ORFV121, a gene unique to parapoxviruses, was shown to encode an inhibitor of NF-B that contributes to ORFV virulence and disease pathogenesis in sheep.…”

Section: Discussionmentioning

confidence: 99%

“…Cells were lysed with 200 l of lysis buffer (50 mM Tris-HCl, pH 7.4, with 150 mM NaCl, 1 mM EDTA, and 1% Triton X-100) and incubated at room temperature for 15 min. Proteins were immunoprecipitated by using the FLAG immunoprecipitation kit (Sigma, St. Louis, MO) by following the manufacturer's protocol or an anti-NF-B-p65 antibody coupled to protein G agarose beads (Upstate) as previously described (12). Immunoprecipitated proteins were resolved by SDS-PAGE, and blots were probed with antibodies against Flag-M2 (no.…”

Section: Cells and Virusesmentioning

confidence: 99%

“…The construction, selection, and purification of OV-IA82Rv121 were performed as previously described (12). The presence of ORFV121 sequence and the absence of Neo/Gus sequences in the purified revertant 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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Section: Discussioncontrasting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Section: Cells and Virusesmentioning

confidence: 99%

Section: Cells and Virusesmentioning

confidence: 99%

mentioning

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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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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Orf virus infection

Bergqvist

Kurban

Abbas

2017

Reviews in Medical Virology

117

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Orf virus (ORFV) is an important pathogen responsible for a highly contagious zoonotic viral infection that threatens those who handle sheep and goats. Orf virus is the prototype of the Parapoxvirus genus, and its resilience in the environment and ability to reinfect its host has contributed to the spread and maintenance of the infection in many species. In healthy humans, the disease usually resolves spontaneously within 3 to 6 weeks. There is no specific treatment and many different approaches such as use of imiquimod, cidofovir, curettage, shave excision, cryotherapy, and electrocautery have all been reported to be successful, without supporting evidence from controlled clinical trials. Throughout its interaction with the different hosts, ORFV has evolved a strategy for immune evasion via the development of an array of virulence factors. The interaction of ORFV with the immune system has been the subject of research for decades. Whole inactivated ORFV has been used as a type of immunomodulating drug; a so called paramunity inducer proposed as both a preventative and a therapeutic immunomodulator across various species. Additional research on the remarkable strategies underlying ORFV infection could lead to improved understanding of skin immunity.

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A Nuclear Inhibitor of NF-κB Encoded by a Poxvirus

Cited by 53 publications

References 46 publications

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

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

Orf virus infection

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