{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:18:19Z","timestamp":1787026699612,"version":"build-2736575974"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,5,4]],"date-time":"2022-05-04T00:00:00Z","timestamp":1651622400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:p>\n                    Endoplasmic reticulum aminopeptidase 1 (ERAP1) is a processing enzyme of antigenic peptides presented to major histocompatibility complex (MHC) class I molecules. ERAP1-dependent trimming of epitope repertoire determines an efficacy of adoptive CD8\n                    <jats:sup>+<\/jats:sup>\n                    T-cell responses in several viral diseases; however, its role in hepatitis B virus (HBV) infection remains unknown. Here, we show that the serum level of ERAP1 in patients with chronic hepatitis B (CHB) (\n                    <jats:italic>n<\/jats:italic>\n                    = 128) was significantly higher than that of healthy controls (\n                    <jats:italic>n<\/jats:italic>\n                    = 44) (8.78 \u00b1 1.82 vs. 3.52 \u00b1 1.61,\n                    <jats:italic>p<\/jats:italic>\n                    &amp;lt; 0.001). Furthermore, peripheral ERAP1 level is moderately correlated with HBV DNA level in patients with CHB (\n                    <jats:italic>r<\/jats:italic>\n                    = 0.731,\n                    <jats:italic>p<\/jats:italic>\n                    &amp;lt; 0.001). HBV-transfected HepG2.2.15 cells had substantially increased ERAP1 expression and secretion than the germline HepG2 cells (\n                    <jats:italic>p<\/jats:italic>\n                    &amp;lt; 0.001). The co-culture of ERAP1-specific inhibitor ERAP1-IN-1 pretreated HepG2.2.15 cells or\n                    <jats:italic>ERAP1<\/jats:italic>\n                    knockdown HepG2.2.15 cells with CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells led to 14\u201324% inhibition of the proliferation of CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells. Finally, liquid chromatography tandem mass spectrometry (LC-MS\/MS) test demonstrated that ERAP1-IN-1 blocks completely the production of a 9-mers peptide (30\u201338, LLDTASALY) derived from Hepatitis B core antigen (HBcAg). The predictive analysis by NetMHCpan-4.1 server showed that human leukocyte antigen (HLA)-C*04:01 is a strong binder for the 9-mers peptide in HepG2.2.15 cells. Taken together, our results demonstrated that ERAP1 trims HBcAg to produce 9-mers LLDTASALY peptides for binding onto HLA-C*04:01 in HepG2.2.15 cells, facilitating the potential activation of CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells.\n                  <\/jats:p>","DOI":"10.3389\/fmicb.2022.829241","type":"journal-article","created":{"date-parts":[[2022,5,4]],"date-time":"2022-05-04T03:55:10Z","timestamp":1651636510000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Endoplasmic Reticulum Aminopeptidase 1 Is Involved in Anti-viral Immune Response of Hepatitis B Virus by Trimming Hepatitis B Core Antigen to Generate 9-Mers Peptides"],"prefix":"10.3389","volume":"13","author":[{"given":"Huanhuan","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingqi","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junfeng","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feier","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faming","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liwen","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,5,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.molimm.2013.06.012","article-title":"ERAP1 structure, function and pathogenetic role in ankylosing spondylitis and other MHC-associated diseases.","volume":"57","author":"Alvarez-Navarro","year":"2014","journal-title":"Mol. Immunol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"3033","DOI":"10.4049\/jimmunol.0903712","article-title":"Endoplasmic reticulum aminopeptidase associated with antigen processing defines the composition and structure of MHC class I peptide repertoire in normal and virus-infected cells.","volume":"184","author":"Blanchard","year":"2010","journal-title":"J. Immunol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1329","DOI":"10.1038\/ng.2007.17","article-title":"Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants.","volume":"39","author":"Burton","year":"2007","journal-title":"Nat. Genet."},{"key":"B4","doi-asserted-by":"publisher","first-page":"17107","DOI":"10.1073\/pnas.0500721102","article-title":"The ER aminopeptidase, ERAP1, trims precursors to lengths of MHC class I peptides by a \u201cmolecular ruler\u201d mechanism.","volume":"102","author":"Chang","year":"2005","journal-title":"Proc Natl Acad Sci U.S.A."},{"key":"B5","doi-asserted-by":"publisher","first-page":"2048","DOI":"10.3389\/fimmu.2019.02048","article-title":"HBV-induced immune imbalance in the development of HCC.","volume":"10","author":"Chen","year":"2019","journal-title":"Front. Immunol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1597","DOI":"10.1158\/0008-5472.CAN-10-3326","article-title":"Natural killer cells efficiently reject lymphoma silenced for the endoplasmic reticulum aminopeptidase associated with antigen processing.","volume":"71","author":"Cifaldi","year":"2011","journal-title":"Cancer Res."},{"key":"B7","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1007\/s00251-018-01098-2","article-title":"A personal retrospective on the mechanisms of antigen processing.","volume":"71","author":"Cresswell","year":"2019","journal-title":"Immunogenetics"},{"key":"B8","doi-asserted-by":"publisher","first-page":"4645","DOI":"10.1128\/JVI.63.11.4645-4652.1989","article-title":"A recombinant hepatitis B core antigen polypeptide with the protamine-like domain deleted self-assembles into capsid particles but fails to bind nucleic acids.","volume":"63","author":"Gallina","year":"1989","journal-title":"J. Virol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"13","DOI":"10.2174\/157016409787847439","article-title":"Cellular Mechanisms that Edit the Immunopeptidome.","volume":"6","author":"Georgiadou","year":"2009","journal-title":"Curr. Proteomics"},{"key":"B10","doi-asserted-by":"publisher","first-page":"21906","DOI":"10.1074\/jbc.M111.239111","article-title":"Secretion of endoplasmic reticulum aminopeptidase 1 is involved in the activation of macrophages induced by lipopolysaccharide and interferon-gamma.","volume":"286","author":"Goto","year":"2011","journal-title":"J. Biol. Chem."},{"key":"B11","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1146\/annurev.immunol.19.1.65","article-title":"Noncytolytic control of viral infections by the innate and adaptive immune response.","volume":"19","author":"Guidotti","year":"2001","journal-title":"Annu. Rev. Immunol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"825","DOI":"10.1126\/science.284.5415.825","article-title":"Viral clearance without destruction of infected cells during acute HBV infection.","volume":"284","author":"Guidotti","year":"1999","journal-title":"Science"},{"key":"B13","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1016\/j.immuni.2007.04.003","article-title":"The final touches make perfect the peptide-MHC class I repertoire.","volume":"26","author":"Hammer","year":"2007","journal-title":"Immunity"},{"key":"B14","first-page":"175","article-title":"Hepatitis B core antigen and antibody.","volume":"30","author":"Hoofnagle","year":"1975","journal-title":"Dev. Biol. Stand."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1499","DOI":"10.1038\/ng.2809","article-title":"New loci associated with chronic hepatitis B virus infection in Han Chinese.","volume":"45","author":"Hu","year":"2013","journal-title":"Nat. Genet."},{"key":"B16","doi-asserted-by":"publisher","first-page":"5839","DOI":"10.4049\/jimmunol.1300220","article-title":"Induction of protective antitumor immunity through attenuation of ERAAP function.","volume":"190","author":"James","year":"2013","journal-title":"J. Immunol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/0042-6822(89)90356-5","article-title":"Expression mechanism of the hepatitis B virus (HBV) C gene and biosynthesis of HBe antigen.","volume":"170","author":"Jean-Jean","year":"1989","journal-title":"Virology"},{"key":"B18","doi-asserted-by":"publisher","first-page":"984","DOI":"10.1038\/ni.2097","article-title":"Human cytomegalovirus microRNA miR-US4-1 inhibits CD8(+) T cell responses by targeting the aminopeptidase ERAP1.","volume":"12","author":"Kim","year":"2011","journal-title":"Nat. Immunol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1128\/jvi.74.1.1-7.2000","article-title":"Hepatitis B virus core gene mutations which block nucleocapsid envelopment.","volume":"74","author":"Koschel","year":"2000","journal-title":"J. Virol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1245","DOI":"10.1007\/s00262-019-02358-0","article-title":"Editing the immunopeptidome of melanoma cells using a potent inhibitor of endoplasmic reticulum aminopeptidase 1 (ERAP1).","volume":"68","author":"Koumantou","year":"2019","journal-title":"Cancer Immunol. Immunother."},{"key":"B21","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1021\/acs.jmedchem.9b00293","article-title":"Discovery of selective inhibitors of endoplasmic reticulum aminopeptidase 1.","volume":"63","author":"Maben","year":"2020","journal-title":"J. Med. Chem."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1269","DOI":"10.1084\/jem.191.8.1269","article-title":"The role of virus-specific CD8(+) cells in liver damage and viral control during persistent hepatitis B virus infection.","volume":"191","author":"Maini","year":"2000","journal-title":"J. Exp. Med."},{"key":"B23","doi-asserted-by":"publisher","first-page":"154518","DOI":"10.1016\/j.cyto.2018.08.012","article-title":"Interferon signaling during Hepatitis B Virus (HBV) infection and HBV-associated hepatocellular carcinoma.","volume":"124","author":"Mani","year":"2019","journal-title":"Cytokine"},{"key":"B24","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1097\/QAD.0000000000000574","article-title":"The HLA-C*04: 01\/KIR2DS4 gene combination and human leukocyte antigen alleles with high population frequency drive rate of HIV disease progression.","volume":"29","author":"Olvera","year":"2015","journal-title":"AIDS"},{"key":"B25","doi-asserted-by":"publisher","first-page":"4832","DOI":"10.1016\/j.bmcl.2013.07.024","article-title":"Novel selective inhibitors of aminopeptidases that generate antigenic peptides.","volume":"23","author":"Papakyriakou","year":"2013","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1169","DOI":"10.1038\/ni859","article-title":"An IFN-gamma-induced aminopeptidase in the ER, ERAP1, trims precursors to MHC class I-presented peptides.","volume":"3","author":"Saric","year":"2002","journal-title":"Nat. Immunol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"6053","DOI":"10.3748\/wjg.v27.i36.6053","article-title":"Treatment of hepatitis B virus infection in children and adolescents.","volume":"27","author":"Stinco","year":"2021","journal-title":"World J. Gastroenterol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"636","DOI":"10.1038\/ni.1728","article-title":"Antigen processing influences HIV-specific cytotoxic T lymphocyte immunodominance.","volume":"10","author":"Tenzer","year":"2009","journal-title":"Nat. Immunol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1128\/jvi.77.1.68-76.2003","article-title":"CD8(+) T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection.","volume":"77","author":"Thimme","year":"2003","journal-title":"J. Virol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1248\/bpb.b19-00857","article-title":"Endoplasmic reticulum aminopeptidase 1 beyond antigenic peptide-processing enzyme in the endoplasmic reticulum.","volume":"43","author":"Tsujimoto","year":"2020","journal-title":"Biol. Pharm. Bull."},{"key":"B31","first-page":"60","article-title":"Pathways of antigen processing and presentation.","volume":"1","author":"Watts","year":"1999","journal-title":"Rev. Immunogenet."},{"key":"B32","doi-asserted-by":"publisher","first-page":"624","DOI":"10.1016\/j.ceb.2008.09.005","article-title":"The quality control of MHC class I peptide loading.","volume":"20","author":"Wearsch","year":"2008","journal-title":"Curr. Opin. Cell Biol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1007\/978-1-4939-9450-2_3","article-title":"Trimming of MHC class I ligands by ERAP aminopeptidases.","volume":"1988","author":"Weimershaus","year":"2019","journal-title":"Methods Mol. Biol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"101099","DOI":"10.1016\/j.eclinm.2021.101099","article-title":"Increased risk of severe clinical course of COVID-19 in carriers of HLA-C*04:01.","volume":"40","author":"Weiner","year":"2021","journal-title":"EClinicalMedicine"},{"key":"B35","year":"2018","journal-title":"Hepatitis B."},{"key":"B36","doi-asserted-by":"publisher","first-page":"e05232","DOI":"10.1016\/j.heliyon.2020.e05232","article-title":"Variation of HLA class I (-A and -C) genes in individuals infected with hepatitis B or hepatitis C virus in Cameroon.","volume":"6","author":"Yengo","year":"2020","journal-title":"Heliyon"},{"key":"B37","doi-asserted-by":"publisher","first-page":"9202","DOI":"10.1073\/pnas.0603095103","article-title":"Endoplasmic reticulum aminopeptidase 1 (ERAP1) trims MHC class I-presented peptides in vivo and plays an important role in immunodominance.","volume":"103","author":"York","year":"2006","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1177","DOI":"10.1038\/ni860","article-title":"The ER aminopeptidase ERAP1 enhances or limits antigen presentation by trimming epitopes to 8-9 residues.","volume":"3","author":"York","year":"2002","journal-title":"Nat. Immunol."}],"updated-by":[{"DOI":"10.3389\/fmicb.2023.1273875","type":"erratum","label":"Erratum","source":"publisher","updated":{"date-parts":[[2023,8,18]],"date-time":"2023-08-18T00:00:00Z","timestamp":1692316800000}}],"container-title":["Frontiers in Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2022.829241\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,18]],"date-time":"2023-08-18T10:11:04Z","timestamp":1692353464000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2022.829241\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,4]]},"references-count":38,"alternative-id":["10.3389\/fmicb.2022.829241"],"URL":"https:\/\/doi.org\/10.3389\/fmicb.2022.829241","relation":{},"ISSN":["1664-302X"],"issn-type":[{"value":"1664-302X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,4]]},"article-number":"829241"}}