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 unexplo...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.展开更多
基金supported by the Central Guidance on Local Science and Technology Development Fund of Tibet(Grant No.XZ202301YD0040C)the National Natural Science Foundation of China(Grant No.32260173)the Youth Program of Natural Science Foundation of Henan Province(Grant No.252300420594).
文摘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.
