PTPN13 Contributes to Ebola Virus Induced Immune Dysregulation via dephosphorylation of IRF3 and PI3K-p85

ABSTRACT: Ebola virus disease (EVD) is characterized by immune dysregulation and damaging hyperinflammation. We aimed to characterize the signaling pathways and regulatory mechanisms dysregulated during EVD. To avoid hyperinflammation, innate immune signaling is regulated by posttranslational modifications, including the process of protein phosphorylation. Here, we show that the Protein tyrosine kinase nonreceptor type 13 (PTPN13) negatively regulates IFNβ while also positively regulating the neutrophil chemoattractant CXCL1. Using vectors encoding mutations on IRF3 phosphorylation sites we identified Y292 on IRF3 as PTPN13 target of dephosphorylation. Knockout of PTPN13 increased IRF3 phosphorylation and expression of IFNβ and IFN-stimulated genes, following poly(I:C) stimulation, suggesting that PTPN13 negatively regulated IFNβ and ISG production via IRF3. Intriguingly, depletion of PTPN13 during Ebola virus (EBOV) infection resulted in decreased IFNβ and ISG induction at later timepoints post-infection, which correlated with increased viral titers, suggesting that increased levels of EBOV can efficiently inhibit the IFN response in the absence of PTPN13. Additionally, PTPN13 knockout cells showed a decrease in the induction of inflammatory chemokines, including CXCL1, late during EBOV infection. These effects could be explained by increased phosphorylation on the regulatory p85 subunit of PI3K. Phosphorylation on p85 promotes its degradation, subsequently enhancing PI3K kinase activity and downstream signaling via AKT. Together our study suggests that PTPN13 is involved in immune regulation and efficient antiviral responses by dephosphorylation of IRF3 and PI3K-p85.

ORGANISM(S): Homo sapiens

PROVIDER: GSE324141 | GEO | 2026/08/12

REPOSITORIES: GEO