{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T11:48:02Z","timestamp":1792496882126,"version":"4.5.0"},"reference-count":44,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2017,5,3]],"date-time":"2017-05-03T00:00:00Z","timestamp":1493769600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"},{"start":{"date-parts":[[2017,5,3]],"date-time":"2017-05-03T00:00:00Z","timestamp":1493769600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2017,6]]},"abstract":"<jats:p>\n                    Interferons (IFNs) are broad antiviral cytokines that exert their function by inducing the transcription of hundreds of IFN\u2010stimulated genes (ISGs). However, little is known about the antiviral potential of these cellular effectors on hepatitis E virus (HEV) infection, the leading cause of acute hepatitis globally. In this study, we profiled the antiviral potential of a panel of important human ISGs on HEV replication in cell culture models by overexpression of an individual ISG. The mechanism of action of the key anti\u2010HEV ISG was further studied. We identified retinoic acid\u2013inducible gene I (RIG\u2010I), melanoma differentiation\u2013associated protein 5, and IFN regulatory factor 1 (IRF1) as the key anti\u2010HEV ISGs. We found that basal expression of RIG\u2010I restricts HEV infection. Pharmacological activation of the RIG\u2010I pathway by its natural ligand 5\u2032\u2010triphosphate RNA potently inhibits HEV replication. Overexpression of RIG\u2010I activates the transcription of a wide range of ISGs. RIG\u2010I also mediates but does not overlap with IFN\u2010\u03b1\u2010initiated ISG transcription. Although it is classically recognized that RIG\u2010I exerts antiviral activity through the induction of IFN production by IRF3 and IRF7, we reveal an IFN\u2010independent antiviral mechanism of RIG\u2010I in combating HEV infection. We found that activation of RIG\u2010I stimulates an antiviral response independent of IRF3 and IRF7 and regardless of IFN production. However, it is partially through activation of the Janus kinase (JAK)\u2013signal transducer and activator of transcription (STAT) cascade of IFN signaling. RIG\u2010I activated two distinct categories of ISGs, one JAK\u2010STAT\u2010dependent and the other JAK\u2010STAT\u2010independent, which coordinately contribute to the anti\u2010HEV activity.\n                    <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>\n                    : We identified RIG\u2010I as an important anti\u2010HEV ISG that can be pharmacologically activated; activation of RIG\u2010I stimulates the cellular innate immunity against HEV regardless of IFN production but partially through the JAK\u2010STAT cascade of IFN signaling. (H\n                    <jats:sc>epatology<\/jats:sc>\n                    2017;65:1823\u20101839).\n                  <\/jats:p>","DOI":"10.1002\/hep.29105","type":"journal-article","created":{"date-parts":[[2017,2,13]],"date-time":"2017-02-13T07:16:48Z","timestamp":1486970208000},"page":"1823-1839","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":94,"title":["RIG\u2010I is a key antiviral interferon\u2010stimulated gene against hepatitis E virus regardless of interferon production"],"prefix":"10.1097","volume":"65","author":[{"given":"Lei","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology,Erasmus MC\u2010University Medical Center,Rotterdam,The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenshi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,Erasmus MC\u2010University Medical Center,Rotterdam,The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunlong","family":"Li","sequence":"additional","affiliation":[{"name":"Medical Faculty,Kunming University of Science and Technology,Kunming,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinying","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,Erasmus MC\u2010University Medical Center,Rotterdam,The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuebang","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,Erasmus MC\u2010University Medical Center,Rotterdam,The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yijin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,Erasmus MC\u2010University Medical Center,Rotterdam,The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"de Man","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,Erasmus MC\u2010University Medical Center,Rotterdam,The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luc J.W.","family":"van der Laan","sequence":"additional","affiliation":[{"name":"Department of Surgery,Erasmus MC\u2010University Medical Center,Rotterdam,The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fen","family":"Huang","sequence":"additional","affiliation":[{"name":"Medical Faculty,Kunming University of Science and Technology,Kunming,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nassim","family":"Kamar","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Organ Transplantation,CHU Rangueil,Toulouse,France"},{"name":"INSERM U1043, IFR\u2010BMT,CHU Purpan,Toulouse,France"},{"name":"University Toulouse III\u2010Paul Sabatier,Toulouse,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maikel P.","family":"Peppelenbosch","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,Erasmus MC\u2010University Medical Center,Rotterdam,The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuwei","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,Erasmus MC\u2010University Medical Center,Rotterdam,The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2017,5,3]]},"reference":[{"key":"hep29105-bib-0001-20241017","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.jhep.2016.02.045","article-title":"Update on hepatitis E virology: implications for clinical practice","volume":"65","year":"2016","journal-title":"J Hepatol"},{"key":"hep29105-bib-0002-20241017","doi-asserted-by":"crossref","first-page":"2477","DOI":"10.1016\/S0140-6736(11)61849-7","article-title":"Hepatitis E","volume":"379","year":"2012","journal-title":"Lancet"},{"key":"hep29105-bib-0003-20241017","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1016\/S1473-3099(08)70255-X","article-title":"Hepatitis E: an emerging infection in developed countries","volume":"8","year":"2008","journal-title":"Lancet Infect Dis"},{"key":"hep29105-bib-0004-20241017","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1084\/jem.20142274","article-title":"Functional IRF3 deficiency in a patient with herpes simplex encephalitis","volume":"212","year":"2015","journal-title":"J Exp Med"},{"key":"hep29105-bib-0005-20241017","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1126\/science.aaa1578","article-title":"Infectious disease. 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