{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T04:22:25Z","timestamp":1785558145782,"version":"3.56.0"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,5,3]],"date-time":"2021-05-03T00:00:00Z","timestamp":1620000000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010226","name":"Department of Education of Guangdong Province","doi-asserted-by":"publisher","award":["2017KTSCX067"],"award-info":[{"award-number":["2017KTSCX067"]}],"id":[{"id":"10.13039\/501100010226","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010226","name":"Department of Education of Guangdong Province","doi-asserted-by":"publisher","award":["2020KZDZX1084"],"award-info":[{"award-number":["2020KZDZX1084"]}],"id":[{"id":"10.13039\/501100010226","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003453","name":"Natural Science Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2018A030307061"],"award-info":[{"award-number":["2018A030307061"]}],"id":[{"id":"10.13039\/501100003453","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82072292"],"award-info":[{"award-number":["82072292"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:p>Human cytomegalovirus (HCMV) is a ubiquitous opportunistic pathogen and can be life-threatening for immunocompromised individuals. There is currently no available vaccine for the prevention of HCMV- associated diseases and most of the available antiviral drugs that target viral DNA synthesis become ineffective in treating HCMV mutants that arise after long-term use in immunocompromised patients. Here, we examined the effects of Eltanexor, a second-generation selective inhibitor of nuclear export (SINE), on HCMV replication. Eltanexor effectively inhibits HCMV replication in human foreskin fibroblasts in a dose-dependent manner. Eltanexor does not significantly inhibit viral entry and nuclear import of viral genomic DNA, but rather suppress the transcript and protein levels of viral immediate-early (IE), early (E) and late (L) genes, and abolishes the production of infectious virions. We further found Eltanexor treatment promotes proteasome-mediated degradation of XPO1, which contributes to the nuclear retention of interferon regulatory factor 3 (IRF-3), resulting in increased expression of type I interferon as well as interferon stimulating genes ISG15 and ISG54. This study reveals a novel antiviral mechanism of Eltanexor which suggests it has potential to inhibit a broad spectrum of viral pathogens.<\/jats:p>","DOI":"10.3389\/fmicb.2021.675112","type":"journal-article","created":{"date-parts":[[2021,5,3]],"date-time":"2021-05-03T04:53:10Z","timestamp":1620017590000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["The Second-Generation XPO1 Inhibitor Eltanexor Inhibits Human Cytomegalovirus (HCMV) Replication and Promotes Type I Interferon Response"],"prefix":"10.3389","volume":"12","author":[{"given":"Yueyan","family":"Liao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangyu","family":"Ke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianyi","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingsong","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,5,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1006\/viro.2000.0448","article-title":"Disruption of PML-associated nuclear bodies by IE1 correlates with efficient early stages of viral gene expression and DNA replication in human cytomegalovirus infection.","volume":"274","author":"Ahn","year":"2000","journal-title":"Virology"},{"key":"B2","doi-asserted-by":"crossref","DOI":"10.1186\/s13045-020-00903-4","article-title":"XPO1-dependent nuclear export as a target for cancer therapy.","volume":"13","author":"Azizian","year":"2020","journal-title":"J. Hematol. Oncol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1053\/j.gastro.2012.10.036","article-title":"Selective inhibitors of nuclear export block pancreatic cancer cell proliferation and reduce tumor growth in mice.","volume":"144","author":"Azmi","year":"2013","journal-title":"Gastroenterology"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1102","DOI":"10.1016\/j.ebiom.2015.07.041","article-title":"Human Exportin-1 is a target for combined Therapy of HIV and AIDS related lymphoma.","volume":"2","author":"Boons","year":"2015","journal-title":"EBioMedicine"},{"key":"B5","first-page":"S6","article-title":"Congenital cytomegalovirus (CMV) epidemiology and awareness.","author":"Cannon","year":"2019","journal-title":"J. Clin. Virol."},{"key":"B6","first-page":"347","article-title":"HIV-1 Rev and related inhibitors.","volume":"42","author":"Cao","year":"2007","journal-title":"Yao Xue Xue Bao"},{"key":"B7","doi-asserted-by":"publisher","first-page":"4509","DOI":"10.1182\/blood.v128.22.4509.4509","article-title":"A Phase 1\/2 study of the second generation selective inhibitor of nuclear export (SINE) compound, KPT-8602, in Patients with relapsed refractory multiple myeloma.","volume":"128","author":"Cornell","year":"2016","journal-title":"Blood"},{"key":"B8","doi-asserted-by":"crossref","DOI":"10.1186\/s40164-015-0002-5","article-title":"Selective inhibitors of nuclear export (SINE) in hematological malignancies.","volume":"4","author":"Das","year":"2015","journal-title":"Exp. Hematol. Oncol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1032","DOI":"10.1128\/jvi.80.2.1032-1037.2006","article-title":"Interferon regulatory factor 3 is necessary for induction of antiviral genes during human cytomegalovirus infection.","volume":"80","author":"DeFilippis","year":"2006","journal-title":"J. Virol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1136","DOI":"10.1038\/nature07975","article-title":"Structural basis for leucine-rich nuclear export signal recognition by CRM1.","volume":"458","author":"Dong","year":"2009","journal-title":"Nature"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1117","DOI":"10.1093\/infdis\/jiz577","article-title":"Letermovir resistance analysis in a clinical trial of cytomegalovirus prophylaxis for hematopoietic stem cell transplant recipients.","volume":"221","author":"Douglas","year":"2020","journal-title":"J. Infect Dis."},{"key":"B12","author":"Edward","year":"2013","journal-title":"Cytomegalovirus"},{"key":"B13","doi-asserted-by":"publisher","first-page":"408","DOI":"10.1128\/jvi.75.1.408-419.2001","article-title":"Interaction of the influenza virus nucleoprotein with the cellular CRM1-mediated nuclear export pathway.","volume":"75","author":"Elton","year":"2001","journal-title":"J. Virol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1051","DOI":"10.1016\/s0092-8674(00)80371-2","article-title":"CRM1 is an export receptor for leucine-rich nuclear export signals.","volume":"90","author":"Fornerod","year":"1997","journal-title":"Cell"},{"key":"B15","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1007\/s00430-012-0269-7","article-title":"Nucleocytoplasmic shuttling and CRM1-dependent MHC class I peptide presentation of human cytomegalovirus pp65.","volume":"201","author":"Frankenberg","year":"2012","journal-title":"Med. Microbiol. Immunol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"5353","DOI":"10.1128\/jvi.02374-08","article-title":"The respiratory syncytial virus matrix protein possesses a Crm1-mediated nuclear export mechanism.","volume":"83","author":"Ghildyal","year":"2009","journal-title":"J. Virol."},{"key":"B17","doi-asserted-by":"crossref","DOI":"10.1128\/mBio.00866-19","article-title":"CRISPR-Cas9 screening of kaposi\u2019s sarcoma-associated herpesvirus-transformed cells identifies XPO1 as a vulnerable target of cancer cells.","volume":"10","author":"Gruffaz","year":"2019","journal-title":"mBio"},{"key":"B18","first-page":"1942","article-title":"Anti tumor activity of selinexor (KPT-330), a first-in-class oral selective inhibitor of nuclear export (SINE) XPO1\/CRM1 antagonist in patients (pts) with relapsed \/ refractory multiple myeloma (MM) Or Waldenstrom\u2019s macroglobulinemia (WM).","volume":"122","author":"Gutierrez","year":"2013","journal-title":"Blood"},{"key":"B19","doi-asserted-by":"publisher","first-page":"2364","DOI":"10.1038\/leu.2016.136","article-title":"Next-generation XPO1 inhibitor shows improved efficacy and in vivo tolerability in hematological malignancies.","volume":"30","author":"Hing","year":"2016","journal-title":"Leukemia"},{"key":"B20","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1128\/mmbr.00040-07","article-title":"Tegument proteins of human cytomegalovirus.","volume":"72","author":"Kalejta","year":"2008","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"B21","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.11466","article-title":"A deep proteomics perspective on CRM1-mediated nuclear export and nucleocytoplasmic partitioning.","volume":"4","author":"Kirli","year":"2015","journal-title":"Elife"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3390\/cells7110221","article-title":"Controlling the gatekeeper: therapeutic targeting of nuclear transport.","volume":"7","author":"Kosyna","year":"2018","journal-title":"Cells"},{"key":"B23","doi-asserted-by":"publisher","first-page":"9112","DOI":"10.1073\/pnas.96.16.9112","article-title":"Leptomycin B inactivates CRM1\/exportin 1 by covalent modification at a cysteine residue in the central conserved region.","volume":"96","author":"Kudo","year":"1999","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B24","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1111\/j.1365-2567.2005.02258.x","article-title":"Toll-like receptor 3 agonist poly(I:C)-induced antiviral response in human corneal epithelial cells.","volume":"117","author":"Kumar","year":"2006","journal-title":"Immunology"},{"key":"B25","doi-asserted-by":"publisher","first-page":"4159","DOI":"10.1128\/mcb.20.11.4159-4168.2000","article-title":"Regulated nuclear-cytoplasmic localization of interferon regulatory factor 3, a subunit of double-stranded RNA-activated factor 1.","volume":"20","author":"Kumar","year":"2000","journal-title":"Mol. Cell Biol."},{"key":"B26","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/S0163-7258(03)00034-2","article-title":"The human cytomegalovirus.","volume":"98","author":"Landolfo","year":"2003","journal-title":"Pharmacol. Ther."},{"key":"B27","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/j.virusres.2012.02.023","article-title":"Human cytomegalovirus UL94 is a nucleocytoplasmic shuttling protein containing two NLSs and one NES.","volume":"166","author":"Liu","year":"2012","journal-title":"Virus Res."},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0087585","article-title":"Preclinical evaluation of the novel, orally bioavailable selective inhibitor of nuclear export (SINE) KPT-335 in spontaneous canine cancer: results of a phase I study.","volume":"9","author":"London","year":"2014","journal-title":"PLoS One"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1870","DOI":"10.1128\/jvi.75.4.1870-1878.2001","article-title":"Human cytomegalovirus with IE-2 (UL122) deleted fails to express early lytic genes.","volume":"75","author":"Marchini","year":"2001","journal-title":"J. Virol."},{"key":"B30","doi-asserted-by":"crossref","DOI":"10.3389\/fmicb.2017.01171","article-title":"CRM1 inhibitors for antiviral therapy.","volume":"8","author":"Mathew","year":"2017","journal-title":"Front. Microbiol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"2025","DOI":"10.1016\/j.jmb.2015.09.025","article-title":"Mechanistic insights from structural analyses of ran-GTPase-driven nuclear export of proteins and RNAs.","volume":"428","author":"Matsuura","year":"2016","journal-title":"J. Mol. Biol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1016\/j.pharmthera.2015.06.002","article-title":"Neuroprotective peptides fused to arginine-rich cell penetrating peptides: neuroprotective mechanism likely mediated by peptide endocytic properties.","volume":"153","author":"Meloni","year":"2015","journal-title":"Pharmacol. Ther."},{"key":"B33","doi-asserted-by":"crossref","DOI":"10.1038\/s41419-020-03303-1","article-title":"Targeting XPO1 enhances innate immune response and inhibits KSHV lytic replication during primary infection by nuclear stabilization of the p62 autophagy adaptor protein.","volume":"12","author":"Meng","year":"2021","journal-title":"Cell Death Dis."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1087","DOI":"10.1126\/science.1173388","article-title":"Crystal structure of the nuclear export receptor CRM1 in complex with Snurportin1 and RanGTP.","volume":"324","author":"Monecke","year":"2009","journal-title":"Science"},{"key":"B35","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2016.00226","article-title":"The Scavenger receptor SREC-I cooperates with toll-like receptors to trigger inflammatory innate immune responses.","volume":"7","author":"Murshid","year":"2016","journal-title":"Front. Immunol."},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3390\/v8030058","article-title":"HTLV-1 rex tunes the cellular environment favorable for viral replication.","volume":"8","author":"Nakano","year":"2016","journal-title":"Viruses"},{"key":"B37","doi-asserted-by":"publisher","first-page":"3700","DOI":"10.1128\/jvi.02442-10","article-title":"Human cytomegalovirus pUS27 G protein-coupled receptor homologue is required for efficient spread by the extracellular route but not for direct cell-to-cell spread.","volume":"85","author":"O\u2019Connor","year":"2011","journal-title":"J. Virol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1016\/j.virol.2005.02.005","article-title":"Nucleocytoplasmic shuttling of the rabies virus P protein requires a nuclear localization signal and a CRM1-dependent nuclear export signal.","volume":"334","author":"Pasdeloup","year":"2005","journal-title":"Virology"},{"key":"B39","doi-asserted-by":"publisher","first-page":"10228","DOI":"10.1128\/jvi.01774-14","article-title":"Verdinexor, a novel selective inhibitor of nuclear export, reduces influenza a virus replication in vitro and in vivo.","volume":"88","author":"Perwitasari","year":"2014","journal-title":"J. Virol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"761","DOI":"10.1016\/j.molcel.2004.11.018","article-title":"Architecture of CRM1\/Exportin1 suggests how cooperativity is achieved during formation of a nuclear export complex.","volume":"16","author":"Petosa","year":"2004","journal-title":"Mol. Cell"},{"key":"B41","doi-asserted-by":"publisher","first-page":"1282","DOI":"10.1016\/j.clinthera.2018.07.006","article-title":"Antiviral therapies for herpesviruses: current agents and new directions.","volume":"40","author":"Poole","year":"2018","journal-title":"Clin. Ther."},{"key":"B42","doi-asserted-by":"publisher","first-page":"1765","DOI":"10.1182\/blood-2012-04-423160","article-title":"Preclinical activity of a novel CRM1 inhibitor in acute myeloid leukemia.","volume":"120","author":"Ranganathan","year":"2012","journal-title":"Blood"},{"key":"B43","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1097\/mot.0000000000000541","article-title":"Drug-resistant cytomegalovirus: clinical implications of specific mutations.","volume":"23","author":"Razonable","year":"2018","journal-title":"Curr. Opin. Organ. Transplant."},{"key":"B44","doi-asserted-by":"publisher","first-page":"11730","DOI":"10.1128\/jvi.02760-06","article-title":"Nuclear export of the human cytomegalovirus tegument protein pp65 requires cyclin-dependent kinase activity and the Crm1 exporter.","volume":"81","author":"Sanchez","year":"2007","journal-title":"J. Virol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1099\/vir.0.83286-0","article-title":"Cloning and sequencing of a highly productive, endotheliotropic virus strain derived from human cytomegalovirus TB40\/E.","volume":"89","author":"Sinzger","year":"2008","journal-title":"J. Gen. Virol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1007\/978-3-540-77349-8_8","article-title":"Functional roles of the human cytomegalovirus essential IE86 protein.","volume":"325","author":"Stinski","year":"2008","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"1303","DOI":"10.1073\/pnas.1217203110","article-title":"Nuclear export inhibition through covalent conjugation and hydrolysis of Leptomycin B by CRM1.","volume":"110","author":"Sun","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B48","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1016\/j.semcancer.2014.03.001","article-title":"Inhibition of CRM1-dependent nuclear export sensitizes malignant cells to cytotoxic and targeted agents.","volume":"27","author":"Turner","year":"2014","journal-title":"Semin. Cancer Biol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"2528","DOI":"10.1158\/1078-0432.ccr-16-1580","article-title":"The second-generation exportin-1 inhibitor KPT-8602 demonstrates potent activity against acute lymphoblastic leukemia.","volume":"23","author":"Vercruysse","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.21037\/sci.2019.02.03","article-title":"The past, present, and future of CRM1\/XPO1 inhibitors.","volume":"6","author":"Wang","year":"2019","journal-title":"Stem. Cell Investig."},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0200043","article-title":"In vitro toxicity and efficacy of verdinexor, an exportin 1 inhibitor, on opportunistic viruses affecting immunocompromised individuals.","volume":"13","author":"Widman","year":"2018","journal-title":"PLoS One"},{"key":"B52","doi-asserted-by":"publisher","first-page":"3673","DOI":"10.1091\/mbc.e12-01-0045","article-title":"NESdb: a database of NES-containing CRM1 cargoes.","volume":"23","author":"Xu","year":"2012","journal-title":"Mol. Biol. Cell"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0102983","article-title":"Novel small molecule XPO1\/CRM1 inhibitors induce nuclear accumulation of TP53, phosphorylated MAPK and apoptosis in human melanoma cells.","volume":"9","author":"Yang","year":"2014","journal-title":"PLoS One"},{"key":"B54","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/j.exphem.2012.09.002","article-title":"Novel selective inhibitors of nuclear export CRM1 antagonists for therapy in mantle cell lymphoma.","volume":"41","author":"Zhang","year":"2013","journal-title":"Exp. Hematol."},{"key":"B55","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1007\/s00280-014-2495-8","article-title":"KPT-330 inhibitor of XPO1-mediated nuclear export has anti-proliferative activity in hepatocellular carcinoma.","volume":"74","author":"Zheng","year":"2014","journal-title":"Cancer Chemother. Pharmacol."}],"container-title":["Frontiers in Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2021.675112\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,3]],"date-time":"2021-05-03T04:53:21Z","timestamp":1620017601000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2021.675112\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,3]]},"references-count":55,"alternative-id":["10.3389\/fmicb.2021.675112"],"URL":"https:\/\/doi.org\/10.3389\/fmicb.2021.675112","relation":{},"ISSN":["1664-302X"],"issn-type":[{"value":"1664-302X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,3]]},"article-number":"675112"}}