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A parapoxviral virion protein inhibits NF-κB signaling early in infection

Poxviruses have evolved unique proteins and mechanisms to counteract the nuclear factor κB (NF-κB) signaling pathway, which is an essential regulatory pathway of host innate immune responses. Here, we describe a NF-κB inhibitory virion protein of orf virus (ORFV), ORFV073, which functions very early...

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Autores principales: Khatiwada, Sushil, Delhon, Gustavo, Nagendraprabhu, Ponnuraj, Chaulagain, Sabal, Luo, Shuhong, Diel, Diego G., Flores, Eduardo F., Rock, Daniel L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5560748/
https://www.ncbi.nlm.nih.gov/pubmed/28787456
http://dx.doi.org/10.1371/journal.ppat.1006561
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author Khatiwada, Sushil
Delhon, Gustavo
Nagendraprabhu, Ponnuraj
Chaulagain, Sabal
Luo, Shuhong
Diel, Diego G.
Flores, Eduardo F.
Rock, Daniel L.
author_facet Khatiwada, Sushil
Delhon, Gustavo
Nagendraprabhu, Ponnuraj
Chaulagain, Sabal
Luo, Shuhong
Diel, Diego G.
Flores, Eduardo F.
Rock, Daniel L.
author_sort Khatiwada, Sushil
collection PubMed
description Poxviruses have evolved unique proteins and mechanisms to counteract the nuclear factor κB (NF-κB) signaling pathway, which is an essential regulatory pathway of host innate immune responses. Here, we describe a NF-κB inhibitory virion protein of orf virus (ORFV), ORFV073, which functions very early in infected cells. Infection with ORFV073 gene deletion virus (OV-IA82Δ073) led to increased accumulation of NF-κB essential modulator (NEMO), marked phosphorylation of IκB kinase (IKK) subunits IKKα and IKKβ, IκBα and NF-κB subunit p65 (NF-κB-p65), and to early nuclear translocation of NF-κB-p65 in virus-infected cells (≤ 30 min post infection). Expression of ORFV073 alone was sufficient to inhibit TNFα induced activation of the NF-κB signaling in uninfected cells. Consistent with observed inhibition of IKK complex activation, ORFV073 interacted with the regulatory subunit of the IKK complex NEMO. Infection of sheep with OV-IA82Δ073 led to virus attenuation, indicating that ORFV073 is a virulence determinant in the natural host. Notably, ORFV073 represents the first poxviral virion-associated NF-κB inhibitor described, highlighting the significance of viral inhibition of NF-κB signaling very early in infection.
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spelling pubmed-55607482017-08-25 A parapoxviral virion protein inhibits NF-κB signaling early in infection Khatiwada, Sushil Delhon, Gustavo Nagendraprabhu, Ponnuraj Chaulagain, Sabal Luo, Shuhong Diel, Diego G. Flores, Eduardo F. Rock, Daniel L. PLoS Pathog Research Article Poxviruses have evolved unique proteins and mechanisms to counteract the nuclear factor κB (NF-κB) signaling pathway, which is an essential regulatory pathway of host innate immune responses. Here, we describe a NF-κB inhibitory virion protein of orf virus (ORFV), ORFV073, which functions very early in infected cells. Infection with ORFV073 gene deletion virus (OV-IA82Δ073) led to increased accumulation of NF-κB essential modulator (NEMO), marked phosphorylation of IκB kinase (IKK) subunits IKKα and IKKβ, IκBα and NF-κB subunit p65 (NF-κB-p65), and to early nuclear translocation of NF-κB-p65 in virus-infected cells (≤ 30 min post infection). Expression of ORFV073 alone was sufficient to inhibit TNFα induced activation of the NF-κB signaling in uninfected cells. Consistent with observed inhibition of IKK complex activation, ORFV073 interacted with the regulatory subunit of the IKK complex NEMO. Infection of sheep with OV-IA82Δ073 led to virus attenuation, indicating that ORFV073 is a virulence determinant in the natural host. Notably, ORFV073 represents the first poxviral virion-associated NF-κB inhibitor described, highlighting the significance of viral inhibition of NF-κB signaling very early in infection. Public Library of Science 2017-08-07 /pmc/articles/PMC5560748/ /pubmed/28787456 http://dx.doi.org/10.1371/journal.ppat.1006561 Text en © 2017 Khatiwada et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Khatiwada, Sushil
Delhon, Gustavo
Nagendraprabhu, Ponnuraj
Chaulagain, Sabal
Luo, Shuhong
Diel, Diego G.
Flores, Eduardo F.
Rock, Daniel L.
A parapoxviral virion protein inhibits NF-κB signaling early in infection
title A parapoxviral virion protein inhibits NF-κB signaling early in infection
title_full A parapoxviral virion protein inhibits NF-κB signaling early in infection
title_fullStr A parapoxviral virion protein inhibits NF-κB signaling early in infection
title_full_unstemmed A parapoxviral virion protein inhibits NF-κB signaling early in infection
title_short A parapoxviral virion protein inhibits NF-κB signaling early in infection
title_sort parapoxviral virion protein inhibits nf-κb signaling early in infection
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5560748/
https://www.ncbi.nlm.nih.gov/pubmed/28787456
http://dx.doi.org/10.1371/journal.ppat.1006561
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