Newcastle Disease Virus V Protein Targets Phosphorylated STAT1 to Block IFN-I Signaling

Abstract

Newcastle disease virus (NDV) V protein is considered as an effector for IFN antagonism, however, the mechanism remains unknown. In this study, the expression of STAT1 and phospho-STAT1 in cells infected with NDV or transfected with V protein-expressing plasmids were analyzed. Our results showed that NDV V protein targets phospho-STAT1 reduction in the cells depends on the stimulation of IFN-α. In addition, a V-deficient genotype VII recombinant NDV strain rZJ1-VS was constructed using reverse genetic technique to confirm the results. The rZJ1-VS lost the ability to reduce phospho-STAT1 and induced higher expression of IFN-responsive genes in infected cells. Furthermore, treatment with an ubiquitin E1 inhibitor PYR-41 demonstrated that phospho-STAT1 reduction was caused by degradation, but not de-phosphorylation. We conclude that NDV V protein targets phospho-STAT1 degradation to block IFN-α signaling, which adds novel knowledge to the strategies used by paramyxoviruses to evade IFN.

IFN-γ establishes interferon-stimulated gene-mediated antiviral state against Newcastle disease virus in chicken fibroblasts

“…and differentiation, as well as antiviral responses. The expressions of a diverse subset of genes identified in this study are in agreement to the previously reported literature where a moderate antiviral functionality is observed against NDV [12,49,50]. Moreover, chIFN-γ is unique in its functionality in the cascade of pathogenic attack against host cells, because it is significantly active in creating an overall antiviral environment against invading pathogens.…”

Newcastle Disease Virus V Protein Degrades Mitochondrial Antiviral Signaling Protein To Inhibit Host Type I Interferon Production via E3 Ubiquitin Ligase RNF5

“…We and others previously reported that NDV V protein can inhibit RLR-mediated interferon signaling by targeting MDA-5, LGP2, STAT1, etc. (22,(25)(26)(27). In this study, we provided several lines of evidence to demonstrate that NDV V protein targets MAVS degradation and subsequently inhibits RLR signaling to benefit virus proliferation at late stages.…”

“…To our surprise, in both WT and MAVS Ϫ/Ϫ 293T cells, the virus titers in the supernatant of NDV-infected cells were higher than those in ΔV ZJ1-infected cells. Since paramyxovirus V protein could target several other RLR signaling pathway-related molecules, including MDA5, LGP2, and STAT1, and inhibit the IFN-␤ signaling pathway (25)(26)(27), knockout of MAVS alone is not sufficient to cover the effect of V deletion. However, interestingly, the finding that MAVS knockout significantly increased virus infection in NDV but not the ΔV ZJ1 infection group suggests NDV V protein is necessary for specifically antagonizing MAVS-mediated innate immunity and virus infection.…”

The molecular basis of the pathogenicity of Newcastle disease virus in chickens

“…11,150 Studies using reverse genetics have also identified the viral replication complex (N, P and L proteins) as influencing the pathogenicity of the virus.…”

“…The V protein may also contribute to the virulence of NDV, by modulating the innate immune response of the host and acting as an alpha interferon antagonist. 10,149,150 In one study, mutations introduced into the V protein of recombinant ND viruses were found to attenuate the virus and decrease the virulence of the viruses in embryonated eggs. 151 A further study supported this theory and found that viruses with mutations in the V protein were attenuated in-vivo.…”