{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T18:16:50Z","timestamp":1790273810311,"version":"4.1.0"},"reference-count":93,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2019,6,4]],"date-time":"2019-06-04T00:00:00Z","timestamp":1559606400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001637","name":"Trinity College Dublin","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001637","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010414","name":"Health Research Board","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010414","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001602","name":"Science Foundation Ireland","doi-asserted-by":"publisher","award":["12\/IA\/1667"],"award-info":[{"award-number":["12\/IA\/1667"]}],"id":[{"id":"10.13039\/501100001602","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2019,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Viruses use a spectrum of immune evasion strategies that enable infection and replication. The acute phase of hepatitis C virus (HCV) infection is characterized by nonspecific and often mild clinical symptoms, suggesting an immunosuppressive mechanism that, unless symptomatic liver disease presents, allows the virus to remain largely undetected. We previously reported that HCV induced the regulatory protein suppressor of cytokine signaling (SOCS)3, which inhibited TNF\u2010\u03b1\u2010mediated inflammatory responses. However, the mechanism by which HCV up\u2010regulates SOCS3 remains unknown. Here we show that the HCV protein, p7, enhances both SOCS3 mRNA and protein expression. A p7 inhibitor reduced SOCS3 induction, indicating that p7\u2032s ion channel activity was required for optimal up\u2010regulation of SOCS3. Short hairpin RNA and chemical inhibition revealed that both the Janus kinase\u2013signal transducer and activator of transcription (JAK\u2010STAT) and MAPK pathways were required for p7\u2010mediated induction of SOCS3. HCV\u2010p7 expression suppressed TNF\u2010\u03b1\u2010mediated I\u03baB\u2010\u03b1 degradation and subsequent NF\u2010\u03baB promoter activity, revealing a new and functional, anti\u2010inflammatory effect of p7. Together, these findings identify a molecular mechanism by which HCV\u2010p7 induces SOCS3 through STAT3 and ERK activation and demonstrate that p7 suppresses proinflammatory responses to TNF\u2010\u03b1, possibly explaining the lack of inflammatory symptoms observed during early HCV infection.\u2014Convery, O., Gargan, S., Kickham, M., Schroder, M., O'Farrelly, C., Stevenson, N. J. The hepatitis C virus (HCV) protein, p7, suppresses inflammatory responses to tumor necrosis factor (TNF)\u2010\u03b1\n                    <jats:italic>via<\/jats:italic>\n                    signal transducer and activator of transcription (STAT)3 and extracellular signal\u2010regulated kinase (ERK)\u2013mediated induction of suppressor of cytokine signaling (SOCS)3. FASEB J. 33, 8732\u20138744 (2019).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201800629rr","type":"journal-article","created":{"date-parts":[[2019,6,4]],"date-time":"2019-06-04T20:00:31Z","timestamp":1559678431000},"page":"8732-8744","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["The hepatitis C virus (HCV) protein, p7, suppresses inflammatory responses to tumor necrosis factor (TNF)\u2010\n                    <i>\u03b1 via<\/i>\n                    signal transducer and activator of transcription (STAT)3 and extracellular signal\u2010regulated kinase (ERK)\u2013mediated induction of suppressor of cytokine signaling (SOCS)3"],"prefix":"10.1096","volume":"33","author":[{"given":"Orla","family":"Convery","sequence":"first","affiliation":[{"name":"School of Biochemistry and Immunology Trinity Biomedical Sciences Institute  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siobhan","family":"Gargan","sequence":"additional","affiliation":[{"name":"School of Biochemistry and Immunology Trinity Biomedical Sciences Institute  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Kickham","sequence":"additional","affiliation":[{"name":"Biology Department Maynooth University  Maynooth Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Schroder","sequence":"additional","affiliation":[{"name":"Biology Department Maynooth University  Maynooth Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cliona","family":"O'Farrelly","sequence":"additional","affiliation":[{"name":"School of Biochemistry and Immunology Trinity Biomedical Sciences Institute  Dublin Ireland"},{"name":"School of Medicine Trinity College Dublin  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nigel J.","family":"Stevenson","sequence":"additional","affiliation":[{"name":"School of Biochemistry and Immunology Trinity Biomedical Sciences Institute  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,6,4]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v20.i11.2876"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.3350\/cmh.2015.21.2.105"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.21902"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2008.02.040"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature07106"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2014.11.007"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01125-09"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.4161\/jkst.25790"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri3581"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2567.2005.02091.x"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-032713-120231"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers6020897"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1202284"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.4103\/1319-3767.108479"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0408824102"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0408707102"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0508531102"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2013.03.041"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.2A1211-608RRRR"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2017.02431"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri2093"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2008.07.010"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00090-15"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2015.342"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1210\/me.2005-0301"},{"key":"e_1_2_8_27_1","first-page":"32538","article-title":"Suppressor of cytokine signaling 3 plays an important role in porcine circovirus type 2 subclinical infection by downregulating proinflammatory responses","volume":"6","author":"Zhu X.","year":"2016","journal-title":"Sd Rep."},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01857-10"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.02-0664fje"},{"key":"e_1_2_8_30_1","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1186\/1471-230X-12-74","article-title":"Hepatitis C virus E2 protein involve in insulin resistance through an impairment of Akt\/PKB and GSK3\u03b2 signaling in hepatocytes","volume":"12","author":"Hsieh M. J.","year":"2012","journal-title":"BMC Gastroenterol."},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2006.11.045"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2005.069674"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.21782"},{"key":"e_1_2_8_34_1","first-page":"1","article-title":"SOCS proteins in development and disease","volume":"2","author":"Trengove M. C.","year":"2013","journal-title":"Am. J. Clin. Exp. Immunol."},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1634\/stemcells.19-5-378"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-291X(02)03071-1"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni931"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2012.04.159"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M308999200"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules181012987"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1207556"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1128\/MMBR.00031-10"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1210394"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00461"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1177\/1753425908094416"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri1391"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.28.16483"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0955-0674(96)80066-4"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2006.10.001"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1203362"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2014.12.016"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20130481"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.166.12.7082"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0306206"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.178.5.2813"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.179.9.5966"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.1099\/vir.0.054338-0"},{"key":"e_1_2_8_58_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1614623114"},{"key":"e_1_2_8_59_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.0030103"},{"key":"e_1_2_8_60_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000778"},{"key":"e_1_2_8_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)63408-6"},{"key":"e_1_2_8_62_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-016-2234-x"},{"key":"e_1_2_8_63_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.323899"},{"key":"e_1_2_8_64_1","doi-asserted-by":"publisher","DOI":"10.4161\/jkst.23931"},{"key":"e_1_2_8_65_1","doi-asserted-by":"publisher","DOI":"10.4161\/jkst.27521"},{"key":"e_1_2_8_66_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.20694"},{"key":"e_1_2_8_67_1","doi-asserted-by":"publisher","DOI":"10.1177\/1947601911407328"},{"key":"e_1_2_8_68_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2007.01.002"},{"key":"e_1_2_8_69_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)00028-5"},{"key":"e_1_2_8_70_1","doi-asserted-by":"publisher","DOI":"10.7150\/ijms.3.47"},{"key":"e_1_2_8_71_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI39133"},{"key":"e_1_2_8_72_1","doi-asserted-by":"publisher","DOI":"10.4161\/jkst.23010"},{"key":"e_1_2_8_73_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.12.6964"},{"key":"e_1_2_8_74_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20012127"},{"key":"e_1_2_8_75_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2004.01.008"},{"key":"e_1_2_8_76_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.171311298"},{"key":"e_1_2_8_77_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00705-016-2892-x"},{"key":"e_1_2_8_78_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.26496"},{"key":"e_1_2_8_79_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.174.5.2494"},{"key":"e_1_2_8_80_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1204372"},{"key":"e_1_2_8_81_1","doi-asserted-by":"publisher","DOI":"10.1053\/jhep.2000.19343"},{"key":"e_1_2_8_82_1","doi-asserted-by":"crossref","first-page":"11329","DOI":"10.1074\/jbc.M410161200","article-title":"Binding of hepatitis C virus envelope protein E2 to CD81 up\u2010regulates matrix metalloproteinase\u20102 in human hepatic stellate cells. J","volume":"280","author":"Mazzocca A.","year":"2005","journal-title":"Biol. Chem."},{"key":"e_1_2_8_83_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12192-013-0405-3"},{"key":"e_1_2_8_84_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00326-16"},{"key":"e_1_2_8_85_1","doi-asserted-by":"publisher","DOI":"10.1099\/vir.0.032581-0"},{"key":"e_1_2_8_86_1","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0106014"},{"key":"e_1_2_8_87_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2005.10.003"},{"key":"e_1_2_8_88_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.06243-11"},{"key":"e_1_2_8_89_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aab2159"},{"key":"e_1_2_8_90_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.26.8.3048-3059.2006"},{"key":"e_1_2_8_91_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.73.6.4713-4720.1999"},{"key":"e_1_2_8_92_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.79.12.7648-7657.2005"},{"key":"e_1_2_8_93_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M010533200"},{"key":"e_1_2_8_94_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2013.06.029"}],"container-title":["The FASEB Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.201800629RR","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1096\/fj.201800629RR","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.201800629RR","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T16:22:56Z","timestamp":1761668576000},"score":1,"resource":{"primary":{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/10.1096\/fj.201800629RR"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,6,4]]},"references-count":93,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2019,8]]}},"alternative-id":["10.1096\/fj.201800629RR"],"URL":"https:\/\/doi.org\/10.1096\/fj.201800629rr","archive":["Portico"],"relation":{},"ISSN":["0892-6638","1530-6860"],"issn-type":[{"value":"0892-6638","type":"print"},{"value":"1530-6860","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,6,4]]},"assertion":[{"value":"2018-04-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-03-28","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-06-04","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}