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Sox4 represses host innate immunity to facilitate pathogen infection by hijacking the TLR signaling networks

Jian Shang1, Yuan Zheng2, Jiayin Mo2

  • 1Guangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University , Guangzhou, China.

Virulence
|February 1, 2021
PubMed

Insights

Sex-determining region Y-box 4 (Sox4) represses Toll-like receptor (TLR) signaling during viral infections. This mechanism, involving inhibition of key signaling molecules and transcription factors, facilitates viral replication by dampening innate immune responses.

Area of Science:

  • Immunology
  • Virology
  • Molecular Biology

Background:

  • Toll-like receptors (TLRs) are crucial for innate immunity, initiating inflammatory and immune responses against pathogens.
  • Dysregulated TLR signaling can lead to detrimental outcomes, highlighting the need for precise control.
  • Balancing TLR activation and suppression is vital for effective pathogen elimination while preventing self-damage.

Purpose of the Study:

  • To elucidate a novel regulatory mechanism within the TLR network during viral infections.
  • To identify key molecular players involved in the host's response to viral pathogens.
  • To understand how viral pathogens evade host innate immunity.

Main Methods:

  • Induction of sex-determining region Y-box 4 (Sox4) expression in response to viral infection in patients and cell cultures.
  • Analysis of Sox4's impact on the expression of Myeloid differentiation primary response gene 88 (MyD88) and various TLRs.
  • Investigation of Sox4's effects on TLR signaling pathways, including TLR/MyD88/IRAK4/TAK1 and TLR/TRIF/TRAF3/TBK1.
  • Assessment of Sox4's interaction with IKKα/α and its influence on NF-κB and Interferon regulatory factors 3/7 (IRF3/7) protein levels.
  • Measurement of downstream effects on Interferon (IFN) and IFN-stimulated gene (ISG) expression.

Main Results:

  • Viral infection induces Sox4 expression, which subsequently represses the TLR signaling network.
  • Sox4 inhibits MyD88 and TLR production by binding to their promoters, reducing gene transcription.
  • Sox4 disrupts TLR signaling pathways by repressing essential components and inhibits NF-κB activation.
  • Sox4 promotes protein degradation of NF-kB and IRF3/7, leading to reduced IFN and ISG expression.
  • These actions collectively facilitate viral replication by suppressing host innate immunity.

Conclusions:

  • Sox4 acts as a key regulator that suppresses host innate immunity during viral infections.
  • Viral pathogens utilize Sox4 to evade immune detection and promote their replication.
  • Understanding this Sox4-mediated mechanism offers insights into host-pathogen interactions and potential therapeutic targets.
Keywords:
EV71Enterovirus 71HCVIAVIFNIFN regulatory factors 3/7IFN-stimulated geneIRF3/7ISGMyD88SEVSox4TLRSToll-like receptorsVSVhepatitis C virusinfluenza A virusinterferonmyeloid differentiation primary response gene 88sendai virussex-determining region Y-box 4vesicular stomatitis virus

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