Abstract
The innate immune cGAS-STING pathway is activated by cytosolic double-stranded DNA (dsDNA) to induce type I interferon (IFN) response, which is essential for mounting the antiviral response. However, STING activation during viral infection is often insufficient to achieve complete viral clearance, suggesting the existence of additional mechanisms that evade its activity. Here, we identified COX2/PGE(2) as a negative regulator of STING activation, particularly in response to arising cytosolic mitochondrial DNA (mtDNA) generated during HSV-1 infection. Mechanistically, PGE(2), through the EP4-cAMP-PKA axis, induces mitophagy to remove defective mitochondria and hence prevent the accumulation of immunostimulatory cytosolic mtDNA, thereby dampening STING-mediated type I IFN and antiviral response. Furthermore, we identified STOML2 as a downstream target of PKA that connects mitochondrial quality control with the regulation of innate immune signaling. Together, our findings establish the COX2/PGE(2)/PKA axis as a negative regulator of mtDNA-STING signaling that may be targeted to potentiate STING-mediated type I IFN and innate immunity.