Abstract

Borna disease virus (BDV) has a non-segmented, negative-stranded RNA genome and causes persistent infection in many animal species. Previous study has shown that the activation of the IκB kinase (IKK)/NF-κB pathway is reduced by BDV infection even in cells expressing constitutively active mutant IKK. This result suggests that BDV directly interferes with the IKK/NF-κB pathway. To elucidate the mechanism for the inhibition of NF-κB activation by BDV infection, we evaluated the cross-talk between BDV infection and the NF-κB pathway. Using Multiple EM for Motif Elicitation analysis, we found that the nucleoproteins of BDV (BDV-N) and NF-κB1 share a common ankyrin-like motif. When THP1-CD14 cells were pre-treated with the identified peptide, NF-κB activation by Toll-like receptor ligands was suppressed. The 20S proteasome assay showed that BDV-N and BDV-N-derived peptide inhibited the processing of NF-κB1 p105 into p50. Furthermore, immunoprecipitation assays showed that BDV-N interacted with NF-κB1 but not with NF-κB2, which shares no common motif with BDV-N. These results suggest BDV-N inhibits NF-κB1 processing by the 20S proteasome through its ankyrin-like peptide sequence, resulting in the suppression of IKK/NF-κB pathway activation. This inhibitory effect of BDV on the induction of the host innate immunity might provide benefits against persistent BDV infection.

Highlights

  • Borna disease virus (BDV) has a non-segmented, negative-stranded RNA genome and causes persistent infection in many animal species

  • These results suggest BDV-N inhibits NF-kB1 processing by the 20S proteasome through its ankyrin-like peptide sequence, resulting in the suppression of IkB kinase (IKK)/NF-kB pathway activation

  • These data could indicate that BDV avoids recognition by pattern recognition receptors (PRRs) that signal through NF-kB or, alternatively, that BDV may be recognized by such PRRs but their signaling is interrupted prior to the activation of NF-kB

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Summary

Introduction

Borna disease virus (BDV) has a non-segmented, negative-stranded RNA genome and causes persistent infection in many animal species. Immunoprecipitation assays showed that BDV-N interacted with NF-kB1 but not with NF-kB2, which shares no common motif with BDV-N These results suggest BDV-N inhibits NF-kB1 processing by the 20S proteasome through its ankyrin-like peptide sequence, resulting in the suppression of IKK/NF-kB pathway activation. This inhibitory effect of BDV on the induction of the host innate immunity might provide benefits against persistent BDV infection. The N protein is concentrated in viral replication factories in the nucleus[22]; it is capable of nucleocytoplasmic shuttling due to a nuclear export signal as well as a nuclear localization signal[23] These properties make N a strong candidate for a viral gene that influences host cell functions, including innate immunity. This difference suggests that BDV infection suppresses the IKK/NF-kB signaling pathway downstream of IKK31

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