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

Tanzeel Yousaf; Jianwen Chen; Wajeeha Naz; Jiaqi Xu; Ying Liu; Junsong Huang; Siqi Yang; Jing Zhang; Iram Amin; Mingxiong Guo; Yunlan Tang; Guihong Sun

doi:10.1016/j.virs.2025.11.012

December 2025

Citation: Tanzeel Yousaf, Jianwen Chen, Wajeeha Naz, Jiaqi Xu, Ying Liu, Junsong Huang, Siqi Yang, Jing Zhang, Iram Amin, Mingxiong Guo, Yunlan Tang, Guihong Sun. RNA and ChIP-sequencing analysis reveals SOX3 suppresses antiviral innate immunity through the AKT1-PTEN signaling axis .VIROLOGICA SINICA, 2025, 40(6) : 921-934. http://dx.doi.org/10.1016/j.virs.2025.11.012

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

Tanzeel Yousaf ^a ,
Jianwen Chen ^a ,
Wajeeha Naz ^a ,
Jiaqi Xu ^a ,
Ying Liu ^b ,
Junsong Huang ^b ,
Siqi Yang ^a ,
Jing Zhang ^a ,
Iram Amin ^c ,
Mingxiong Guo ^b ,
Yunlan Tang ^{d
,,} ,
Guihong Sun ^{a,e
,,}

a. Taikang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China;
b. Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China;
c. Centre of Excellence in Molecular Biology (CEMB), University of the Punjab, Lahore 53700, Pakistan;
d. Henan Provincial People's Hospital, Henan Eye Hospital, Henan Eye Institute, People's Hospital of Zhengzhou University, Henan University People's Hospital, Zhengzhou 450003, China;
e. Hubei Provincial Key Laboratory of Allergy and Immunology, Wuhan 430071, China

Corresponding author: Yunlan Tang, 16110700022@fudan.edu.cn
Guihong Sun, ghsunlab@whu.edu.cn
Received Date: 17 April 2025
Accepted Date: 27 November 2025
Available online: 05 December 2025

Abstract

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.

Electronic Supplementary Material

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

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

Corresponding author: Yunlan Tang, 16110700022@fudan.edu.cn

Corresponding author: Guihong Sun, ghsunlab@whu.edu.cn

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