{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T01:03:37Z","timestamp":1781831017218,"version":"3.54.5"},"update-to":[{"DOI":"10.1371\/journal.ppat.1012895","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,1,28]],"date-time":"2025-01-28T00:00:00Z","timestamp":1738022400000}}],"reference-count":101,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2025,1,21]],"date-time":"2025-01-21T00:00:00Z","timestamp":1737417600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["1104622N"],"award-info":[{"award-number":["1104622N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["G060119N"],"award-info":[{"award-number":["G060119N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["G081125N"],"award-info":[{"award-number":["G081125N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007229","name":"Bijzonder Onderzoeksfonds UGent","doi-asserted-by":"publisher","award":["GOA015-23"],"award-info":[{"award-number":["GOA015-23"]}],"id":[{"id":"10.13039\/501100007229","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007229","name":"Bijzonder Onderzoeksfonds UGent","doi-asserted-by":"publisher","award":["BOF24Y2021017"],"award-info":[{"award-number":["BOF24Y2021017"]}],"id":[{"id":"10.13039\/501100007229","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Gap junctions (GJs) play a pivotal role in intercellular communication between eukaryotic cells, including transfer of biomolecules that contribute to the innate and adaptive immune response. However, if, how and why\u00a0viruses affect gap junction intercellular communication (GJIC) remains largely unexplored. Here, we describe how the alphaherpesvirus pseudorabies virus (PRV) triggers ERK1\/2-mediated phosphorylation of the main gap junction component connexin 43 (Cx43) and closure of GJIC, which depends on the viral protein pUL46. Consequently, a UL46null PRV mutant is unable to phosphorylate Cx43 or inhibit GJIC and displays reduced intercellular spread, which is effectively rescued by pharmacological inhibition of GJIC. Intercellular spread of UL46null PRV is also rescued by inhibition of the stimulator of interferon genes (STING), suggesting that pUL46-mediated suppression of GJIC contributes to intercellular virus spread by hindering intercellular communication that activates STING. The current study identifies key viral and cellular proteins involved in alphaherpesvirus-mediated suppression of GJIC and reveals that GJIC inhibition enhances virus intercellular spread, thereby opening new avenues for the design of targeted antiviral therapies.<\/jats:p>","DOI":"10.1371\/journal.ppat.1012895","type":"journal-article","created":{"date-parts":[[2025,1,21]],"date-time":"2025-01-21T18:33:54Z","timestamp":1737484434000},"page":"e1012895","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":9,"title":["Pseudorabies virus infection triggers pUL46-mediated phosphorylation of connexin-43 and closure of gap junctions to promote intercellular virus spread"],"prefix":"10.1371","volume":"21","author":[{"given":"Alexander","family":"Tishchenko","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicol\u00e1s","family":"Romero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cliff","family":"Van Waesberghe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonas L.","family":"Delva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Vickman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory A.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas C.","family":"Mettenleiter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter","family":"Fuchs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara G.","family":"Klupp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4993-6857","authenticated-orcid":true,"given":"Herman W.","family":"Favoreel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,1,21]]},"reference":[{"issue":"1","key":"ppat.1012895.ref001","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.bbamem.2017.05.016","article-title":"Gap junction gene and protein families: connexins, innexins, and pannexins","author":"EC Beyer","year":"2018","journal-title":"Biochim Biophys Acta Biomembr"},{"issue":"1","key":"ppat.1012895.ref002","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/s00441-012-1485-6","article-title":"Gap-junction-mediated cell-to-cell communication","volume":"352","author":"J-C Herv\u00e9","year":"2013","journal-title":"Cell Tissue Res"},{"issue":"5","key":"ppat.1012895.ref003","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1007\/s00427-004-0403-7","article-title":"Connexin43 orthologues in vertebrates: phylogeny from fish to man","volume":"214","author":"MAG van der Heyden","year":"2004","journal-title":"Dev Genes Evol"},{"issue":"5","key":"ppat.1012895.ref004","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.3390\/ijms19051296","article-title":"Connexins: synthesis, post-translational modifications, and trafficking in health and disease","volume":"19","author":"T Aasen","year":"2018","journal-title":"Int J Mol Sci"},{"issue":"2","key":"ppat.1012895.ref005","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.bbamem.2004.09.009","article-title":"Connexin phosphorylation as a regulatory event linked to gap junction internalization and degradation","author":"DW Laird","year":"2005","journal-title":"Biochim Biophys Acta"},{"issue":"1","key":"ppat.1012895.ref006","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.bbamem.2017.04.008","article-title":"Spatio-temporal regulation of connexin43 phosphorylation and gap junction dynamics","author":"JL Solan","year":"2018","journal-title":"Biochim Biophys Acta Biomembr"},{"key":"ppat.1012895.ref007","doi-asserted-by":"crossref","DOI":"10.3389\/fphar.2013.00130","article-title":"Managing the complexity of communication: regulation of gap junctions by post-translational modification","volume":"4","author":"L Axelsen","year":"2013","journal-title":"Front Pharmacol"},{"issue":"21","key":"ppat.1012895.ref008","doi-asserted-by":"crossref","first-page":"3619","DOI":"10.1242\/jcs.200667","article-title":"Role of connexin 43 in different forms of intercellular communication - 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