RNA and ChIP-sequencing analysis reveals SOX3 suppresses antiviral innate immunity through the AKT1-PTEN signaling axis.

The transcription factor Sex-determining region Y-box protein 3 (SOX3) is well known for its critical roles in sex determination and cell differentiation; however, its function in antiviral innate immunity remains unexplored. This study uncovered how SOX3, induced by viral infections, modulates type I interferon (IFN-I) responses. RNA sequencing, quantitative PCR, and immunoblot analysis collectively revealed that SOX3 overexpression suppresses virus-induced interferon beta 1(IFN-β) promoter activation and significantly inhibits the expression of key antiviral interferon-stimulated genes (ISGs), including ISG15 and interferon induced protein with tetratricopeptide repeats 1 (IFIT1). Conversely, the knockdown of SOX3 enhanced IFN-β production and ISGs expression, confirming its role as a negative regulator of antiviral immunity. Mechanistically, chromatin immunoprecipitation sequencing (ChIP-seq) identified SOX3 binding specifically at the AKT serine/threonine kinase 1 (AKT1) locus. Further analysis demonstrated that SOX3 directly upregulates AKT1 expression, subsequently increasing phosphorylation and inactivation of the tumor suppressor phosphatase and tensin homolog (PTEN). Inactivation of PTEN inhibited interferon regulatory factor 3 (IRF3) nuclear translocation, leading to reduced IFN-β expression. Thus, our findings uncover a previously uncharacterized SOX3-AKT1-PTEN signaling axis in the regulation of antiviral innate immunity, providing new insights into immune evasion strategies and highlighting potential therapeutic targets to enhance antiviral responses.