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Suppression of antiviral innate immunity by the COX2-PGE2-PKA signaling axis by inhibiting the cytosolic mtDNA-dependent activation of STING

ABSTRACT: The innate immune cGAS-STING pathway is activated by cytosolic doubled-stranded DNA (dsDNA) to induce type I interferon response, which is essential for antiviral and antitumor immunity. However, intrinsic STING activation during viral infection or within the tumor microenvironment is often insufficient to achieve complete viral clearance or tumor regression, indicating the presence of additional mechanisms that evades its activity. Here, we identified COX2/PGE2 as an intrinsic negative regulator of STING activation, particularly in response to cytosolic mitochondrial DNA (mtDNA) generated during HSV-1 infection. Mechanistically, we demonstrated that PGE2 signals through the EP4-PKA axis to induce mitophagy and facilitate the clearance of immunostimulatory cytosolic mtDNA, thereby dampening STING-mediated antiviral response. Furthermore, we discovered STOML2 as a direct downstream target of PKA, thereby linking mitochondrial quality control to innate immune signaling. Together, our findings established the COX2/PGE2/PKA axis as an intrinsic negative regulator of STING signaling, which may be targeted to potentiate STING-mediated antiviral and antitumor immunity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE324662 | GEO | 2026/03/16

REPOSITORIES: GEO

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Project description:The goal of this analysis was to utilize microarray profiling to identify basal alterations in gene expression in response to TFAM depletion and mtDNA stress. Mitochondrial DNA (mtDNA) is normally present at thousands of copies per cell and is packaged into several hundred higher-order structures termed nucleoids. The abundant mtDNA-binding protein, TFAM (transcription factor A,mitochondrial), regulates nucleoid architecture, abundance and segregation. Complete mtDNA depletion profoundly impairs oxidative phosphorylation, triggering calcium-dependent stress signalling and adaptive metabolic responses. However, the cellular responses to mtDNA instability, a physiologically relevant stress observed in many human diseases and ageing, remain poorly defined. Here we show that moderate mtDNA stress elicited by TFAM deficiency engages cytosolic antiviral signalling to enhance the expression of a subset of interferon-stimulated genes. Mechanistically, we find that aberrant mtDNA packaging promotes escape of mtDNA into the cytosol, where it engages the DNA sensor cGAS (also known as MB21D1) and promotes STING (also known as TMEM173)–IRF3-dependent signalling to elevate interferon-stimulated gene expression, potentiate type I interferon responses and confer broad viral resistance. Furthermore, we demonstrate that herpesviruses induce mtDNA stress, which enhances antiviral signalling and type I interferon responses during infection. Our results further demonstrate that mitochondria are central participants in innate immunity, identify mtDNA stress as a cell-intrinsic trigger of antiviral signaling and suggest that cellular monitoring of mtDNA homeostasis cooperates with canonical virus sensing mechanisms to fully engage antiviral innate immunity. Murine embryonic fibroblasts were isolated from wild-type or Tfam+/- E13.5 littermate embryos. RNA from passage-matched wild-type and Tfam+/- MEF lines was extracted in duplicate and hybridized onto Affymetrix microarrays. Four arrays were performed in total with two technical replicates per genotype.

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Suppression of antiviral innate immunity by the COX2-PGE2-PKA signaling axis by inhibiting the cytosolic mtDNA-dependent activation of STING

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