4 years ago

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

Diego G. Diel, Eduardo F. Flores, Gustavo Delhon, Shuhong Luo, Daniel L. Rock, Sushil Khatiwada, Sabal Chaulagain, Ponnuraj Nagendraprabhu

by Sushil Khatiwada, Gustavo Delhon, Ponnuraj Nagendraprabhu, Sabal Chaulagain, Shuhong Luo, Diego G. Diel, Eduardo F. Flores, Daniel L. Rock

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.

Publisher URL: http://journals.plos.org/plosone/article

DOI: 10.1371/journal.ppat.1006561

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