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Background <p>Post-translational modifications (PTMs) play a critical role in regulating innate immune responses, including type I interferon (IFN) production and JAK-STAT pathway activation. However, the role of deSUMOylation in antiviral defense remains unclear.</p> Results <p>We identify Sentrin/SUMO-specific protease 5 (SENP5) as a positive regulator of the phosphorylation of STAT2 in JAK-STAT pathway via its deSUMOylation activity, thus inhibiting VSV or HSV-1 replication, and strengthening the antiviral activity of IFN-α. Further investigation reveals that SENP5-mediated deSUMOylation of Aurora kinase A (AURKA) alleviates its inhibition of STAT2 phosphorylation and antiviral innate immunity. Finally, AURKA suppresses STAT2 phosphorylation, and negatively regulates antiviral innate immunity by enhancing the activity of protein phosphatase 2&#xa0;A (PP2A).</p> Conclusions <p>Our study demonstrates that SENP5 upregulates STAT2 phosphorylation via the AURKA–PP2A–STAT2 axis, and uncovers a previously uncharacterized role of SENP5 in regulating antiviral innate immunity.</p>

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SENP5 enhances antiviral innate immunity by promoting AURKA-dependent STAT2 phosphorylation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月13日

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  • Shuyi Song,
  • Yuwei Kan,
  • Minghui Zhou,
  • Yanjun Jiang,
  • Yitian Tang,
  • Hongchun Luo,
  • Yuan Hu

摘要

Background

Post-translational modifications (PTMs) play a critical role in regulating innate immune responses, including type I interferon (IFN) production and JAK-STAT pathway activation. However, the role of deSUMOylation in antiviral defense remains unclear.

Results

We identify Sentrin/SUMO-specific protease 5 (SENP5) as a positive regulator of the phosphorylation of STAT2 in JAK-STAT pathway via its deSUMOylation activity, thus inhibiting VSV or HSV-1 replication, and strengthening the antiviral activity of IFN-α. Further investigation reveals that SENP5-mediated deSUMOylation of Aurora kinase A (AURKA) alleviates its inhibition of STAT2 phosphorylation and antiviral innate immunity. Finally, AURKA suppresses STAT2 phosphorylation, and negatively regulates antiviral innate immunity by enhancing the activity of protein phosphatase 2 A (PP2A).

Conclusions

Our study demonstrates that SENP5 upregulates STAT2 phosphorylation via the AURKA–PP2A–STAT2 axis, and uncovers a previously uncharacterized role of SENP5 in regulating antiviral innate immunity.