{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T02:45:18Z","timestamp":1772160318375,"version":"3.50.1"},"reference-count":38,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2023,10,27]],"date-time":"2023-10-27T00:00:00Z","timestamp":1698364800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP22fk0210108"],"award-info":[{"award-number":["JP22fk0210108"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FEBS Journal"],"published-print":{"date-parts":[[2024,3]]},"abstract":"<jats:p>During the replication of viral genomes, RNA viruses produce double\u2010stranded RNA (dsRNA), through the activity of their RNA\u2010dependent RNA polymerases (RdRps) as viral replication intermediates. Recognition of viral dsRNA by host pattern recognition receptors \u2013 such as retinoic acid\u2010induced gene\u2010I (RIG\u2010I)\u2010like receptors and Toll\u2010like receptor 3 \u2013 triggers the production of interferon (IFN)\u2010\u03b2 via the activation of IFN regulatory factor (IRF)\u20103. It has been proposed that, during the replication of viral genomes, each of RIG\u2010I and melanoma differentiation\u2010associated gene 5 (MDA5) form homodimers for the efficient activation of a downstream signalling pathway in host cells. We previously reported that, in the non\u2010neoplastic human hepatocyte line PH5CH8, the RdRp NS5B derived from hepatitis C virus (HCV) could induce IFN\u2010\u03b2 expression by its RdRp activity without the actual replication of viral genomes. However, the exact mechanism by which HCV NS5B produced IFN\u2010\u03b2 remained unknown. In the present study, we first showed that NS5B derived from another Flaviviridae family member, GB virus B (GBV\u2010B), also possessed the ability to induce IFN\u2010\u03b2 in PH5CH8 cells. Similarly, HCV NS5B, but not its G317V mutant, which lacks RdRp activity, induced the dimerization of MDA5 and subsequently the activation of IRF\u20103. Interestingly, immunofluorescence analysis showed that HCV NS5B produced dsRNA. Like HCV NS5B, GBV\u2010B NS5B also triggered the production of dsRNA and subsequently the dimerization of MDA5. Taken together, our results show that HCV NS5B triggers an MDA5\u2010mediated innate immune response by producing dsRNA without the replication of viral genomes in human hepatocytes.<\/jats:p>","DOI":"10.1111\/febs.16980","type":"journal-article","created":{"date-parts":[[2023,10,20]],"date-time":"2023-10-20T20:48:30Z","timestamp":1697834910000},"page":"1119-1130","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Hepatitis C virus\n                    <scp>NS5B<\/scp>\n                    triggers an\n                    <scp>MDA5<\/scp>\n                    \u2010mediated innate immune response by producing\n                    <scp>dsRNA<\/scp>\n                    without the replication of viral genomes"],"prefix":"10.1111","volume":"291","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2353-3024","authenticated-orcid":false,"given":"Hiromichi","family":"Dansako","sequence":"first","affiliation":[{"name":"Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences Okayama University  Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masanori","family":"Ikeda","sequence":"additional","affiliation":[{"name":"Division of Biological Information Technology, Joint Research Center for Human Retrovirus Infection Kagoshima University  Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasuo","family":"Ariumi","sequence":"additional","affiliation":[{"name":"Management Department of Biosafety, Laboratory Animal, and Pathogen Bank National Institute of Infectious Diseases  Tokyo 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