Current progress on innate immune evasion mediated by Npro protein of pestiviruses

Abstract

Interferon (IFN), the most effective antiviral cytokine, is involved in innate and adaptive immune responses and is essential to the host defense against virus invasion. Once the host was infected by pathogens, the pathogen-associated molecular patterns (PAMPs) were recognized by the host pattern recognition receptors (PRRs), which activates interferon regulatory transcription factors (IRFs) and nuclear factor-kappa B (NF-κB) signal transduction pathway to induce IFN expression. Pathogens have acquired many strategies to escape the IFN-mediated antiviral immune response. Pestiviruses cause massive economic losses in the livestock industry worldwide every year. The immune escape strategies acquired by pestiviruses during evolution are among the major difficulties in its control. Previous experiments indicated that Erns, as an envelope glycoprotein unique to pestiviruses with RNase activity, could cleave viral ss- and dsRNAs, therefore inhibiting the host IFN production induced by viral ss- and dsRNAs. In contrast, Npro, the other envelope glycoprotein unique to pestiviruses, mainly stimulates the degradation of transcription factor IRF-3 to confront the IFN response. This review mainly summarized the current progress on mechanisms mediated by Npro of pestiviruses to antagonize IFN production.

Keywords: immune evasion; innate immunity; interferon (IFN); pestivirus; viral proteins.

Figure 1

N^pro blocks the host’s IFN-activated immune response by degradation of IRF3. Upon viral infection, pathogenic associated molecular patterns (PAMPs) are recognized by cellular pattern recognition receptors (PRRs). A series of cellular pathways were activated subsequently to promote the translocation of phosphorylated IRF3 into the nucleus and initiate the transcription of type I interferon genes by binding to IFN-α/β promoters. N^pro could interact with IRF3 before it’s phosphorylation-induced activation, leading to the ubiquitination and proteasomal degradation of IRF-3 and subsequent inhibition of the type I interferon response.

Figure 2

N competes with NF-κB to bind with IκBα. Prior to stimulation, NF-κB remains an inactive state in the cytoplasm due to its interaction with IκBα, which masks the unclear localization signals of NF-κB. NF-κB/IκBα complex is activated by phosphorylation in response to various stimuli, such as viral and bacterial pathogens. In this case, IκBα is phosphorylated at Ser32 and Ser36 by the IKKβ subunit following the activation of IKK complex. Then, the E3 ubiquitin ligase complex, SCFβ−TRCP, ubiquitinates IκBα and targets it for degradation by the 26S proteasome, leading to the release of NF-κB for nuclear translocation. However, NF-κB activation induces rapid resynthesis of IκBα, which translocates to the nucleus, dissociates NF-κB from DNA and transports NF-κB to the cytoplasm in a nuclear export sequence-dependent process.