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 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.