Quantitative Proteomics Reveals a Novel Role of the E3 Ubiquitin-Protein Ligase FANCL in the Activation of the Innate Immune Response through Regulation of TBK1 Phosphorylation during Peste des Petits Ruminants Virus Infection

Peste
des petits ruminants virus (PPRV) infection causes considerable
innate immunosuppression in its host, which promotes viral replication.
However, how the host rescues the innate immune response to counteract
this immunosuppression during viral replication remains largely unknown.
To explore the mechanisms of how a host counteracts PPRV-mediated
innate immunosuppression, a high-throughput quantitation proteomic
approach (isobaric tags for relative and absolute quantitation in
conjunction with LC–MS/MS) was used to investigate the proteome
landscape of goat fetal fibroblasts (GFFs) in response to PPRV infection.
Eventually, 497 upregulated proteins and 358 downregulated proteins
were identified. Many of the differentially expressed proteins were
enriched in immune-related pathways. Blocking the activation of the
innate immune response with a specific inhibitor BX795 in GFFs remarkably
promoted PPRV replication, suggesting the significant antiviral role
of the enriched immune-related pathways. The GO enrichment analysis
showed that the host protein FANCL revealed a similar expression pattern
to these innate immune-related proteins. In addition, the analysis
of protein–protein interaction networks reveals a potential
relationship between FANCL and the innate immune pathway. We determined
that FANCL inhibited PPRV infection by enhancing type I interferon
(IFN) and IFN-stimulated gene expression. Further investigation determined
that FANCL induced type I IFN production by promoting TBK1 phosphorylation,
thus impairing PPRV-mediated immunosuppression.