{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T20:07:01Z","timestamp":1775678821291,"version":"3.50.1"},"posted":{"date-parts":[[2026,4,6]]},"group-title":"Cell Biology","reference-count":59,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T00:00:00Z","timestamp":1775433600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01DE033909"],"award-info":[{"award-number":["R01DE033909"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,6]]},"abstract":"<jats:title>SUMMARY<\/jats:title>\n                <jats:p>\n                  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\n                  <jats:sub>2<\/jats:sub>\n                  as a negative regulator of STING activation, particularly in response to arising cytosolic mitochondrial DNA (mtDNA) generated during HSV-1 infection. Mechanistically, PGE\n                  <jats:sub>2<\/jats:sub>\n                  , 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\n                  <jats:sub>2<\/jats:sub>\n                  \/PKA axis as a negative regulator of mtDNA-STING signaling that may be targeted to potentiate STING-mediated type I IFN and innate immunity.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Abstract Figure<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:label>Graphical abstract<\/jats:label>\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"716411v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.64898\/2026.04.03.716411","type":"posted-content","created":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T06:25:21Z","timestamp":1775543121000},"source":"Crossref","is-referenced-by-count":0,"title":["The COX2-PGE2-PKA Axis Suppresses Antiviral Immunity by Inhibiting mtDNA-Dependent STING Activation"],"prefix":"10.64898","author":[{"given":"Pham Thuy Tien","family":"Vo","sequence":"first","affiliation":[{"name":"Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA"},{"name":"Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julien","family":"Cicero","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology, School of Biological Sciences, University of California, San Diego, La Jolla, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zichen","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA"},{"name":"Department of Chemistry and Biochemistry, University of California, La Jolla, CA, UCA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroyuki","family":"Hakozaki","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of California, La Jolla, CA, UCA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1282-734X","authenticated-orcid":false,"given":"Thomas S","family":"Hoang","sequence":"additional","affiliation":[{"name":"Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA"},{"name":"Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sendi","family":"Rafael Adame-Garcia","sequence":"additional","affiliation":[{"name":"Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA"},{"name":"Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dana J.","family":"Ramms","sequence":"additional","affiliation":[{"name":"Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA"},{"name":"Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6014-1911","authenticated-orcid":false,"given":"Kuniaki","family":"Sato","sequence":"additional","affiliation":[{"name":"Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA"},{"name":"Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erica","family":"Stevenson","sequence":"additional","affiliation":[{"name":"Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA, USA"},{"name":"J. David Gladstone Institutes, San Francisco, CA, USA"},{"name":"Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA, USA"},{"name":"J. David Gladstone Institutes, San Francisco, CA, USA"},{"name":"Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katie","family":"Fan","sequence":"additional","affiliation":[{"name":"Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA"},{"name":"Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Danielle L.","family":"Swaney","sequence":"additional","affiliation":[{"name":"Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA, USA"},{"name":"J. David Gladstone Institutes, San Francisco, CA, USA"},{"name":"Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4902-337X","authenticated-orcid":false,"given":"Nevan J.","family":"Krogan","sequence":"additional","affiliation":[{"name":"Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA, USA"},{"name":"J. David Gladstone Institutes, San Francisco, CA, USA"},{"name":"Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johannes","family":"Sch\u00f6neberg","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA"},{"name":"Department of Chemistry and Biochemistry, University of California, La Jolla, CA, UCA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9802-1955","authenticated-orcid":false,"given":"Uri","family":"Manor","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology, School of Biological Sciences, University of California, San Diego, La Jolla, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. 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