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

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. 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). 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.