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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,8,25]]},"abstract":"<jats:p>Cells respond to viral infection by induction of numerous innate and other host responses to block infection in that cell and surrounding cells. The mechanism(s) by which nuclear replicating DNA viruses and certain RNA viruses elicit responses through the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) cytoplasmic DNA sensor has been elusive. We report here that early events during herpes simplex virus 1 infection induce blebbing of nuclear DNA into the cytoplasm, recruitment of cGAS colocalization with the cytoplasmic DNA, activation of interferon regulatory factor 3, and induction of type 1 human interferon in normal human fibroblasts and keratinocytes. With HSV-1, this is dependent on viral binding and fusion with the surface membrane but independent of transport of the input viral DNA to the nucleus. Infections by herpes simplex virus 2, human cytomegalovirus, or human parainfluenza virus 3 also induce nuclear DNA blebbing, consistent with entry by surface fusion inducing this effect. Extrusion of nuclear DNA through nuclear envelope breaks upon viral entry by fusion represents a mechanism for cells to respond to the physical and\/or molecular changes in the infected cell during infection.<\/jats:p>","DOI":"10.1073\/pnas.2614472123","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T17:59:27Z","timestamp":1787075967000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Expulsion of nuclear DNA to the cytoplasm after viral entry: A mechanism for activation of the cGAS pathway"],"prefix":"10.1073","volume":"123","author":[{"given":"Nicol\u00e1s","family":"Romero","sequence":"first","affiliation":[{"name":"Department of Microbiology, Blavatnik Institute, Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyung Suk","family":"Oh","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Blavatnik Institute, Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Max E.","family":"Mertens","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Blavatnik Institute, Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Ericsson","sequence":"additional","affiliation":[{"name":"Electron Microscopy Core, Department of Cell Biology, Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle N.","family":"Stearns","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons","place":["New York"]},{"name":"Center for Host\u2013Pathogen Interaction, Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons","place":["New York"]},{"name":"Department of Physiology and Cellular Biophysics, Columbia University Vagelos College of Physicians and Surgeons","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1796-8320","authenticated-orcid":false,"given":"Anne","family":"Moscona","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons","place":["New York"]},{"name":"Center for Host\u2013Pathogen Interaction, Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons","place":["New York"]},{"name":"Department of Physiology and Cellular Biophysics, Columbia University Vagelos College of Physicians and Surgeons","place":["New York"]},{"name":"Department of Microbiology and Immunology, Columbia University Vagelos College of Physicians and Surgeons","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1554-6236","authenticated-orcid":false,"given":"David M.","family":"Knipe","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Blavatnik Institute, Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,8,18]]},"reference":[{"key":"e_1_3_4_1_2","first-page":"227","volume-title":"Fields Virology, Volume 4: Fundamentals","author":"Iwasaki A.","year":"2024","unstructured":"A. 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