ID1 boosts antiviral immunity by countering PRMT5-mediated STING methylation

The stimulator of interferon genes (STING) is a vital protein for the activation of the type I interferon signaling pathway. Despite its critical role in immune response, the regulatory role of methylation in STING activation remains unclear. This study demonstrated that the inhibitor of DNA binding 1 (ID1) enhanced STING-mediated gene expression during viral infection. Mechanistically, protein arginine methyltransferase 5 (PRMT5) interacts with STING and facilitates symmetric dimethylation at the Arg281 residue, thereby inhibiting STING activation. Conversely, methylation-defective STING mutants at Arg281 exhibited increased activity. Moreover, viral infections upregulated ID1 expression, which disrupts the PRMT5-STING interaction and alleviates the PRMT5-mediated inhibition of STING. Importantly, EPZ015666, a selective PRMT5 inhibitor, substantially enhanced antiviral immune responses in vivo and in vitro. These findings unveil an unreported regulatory mechanism in which ID1 and PRMT5 modulate STING activity and highlight EPZ015666 as a promising therapeutic candidate for antiviral interventions.