{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T15:47:04Z","timestamp":1792165624376,"version":"4.4.0"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T00:00:00Z","timestamp":1772582400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100011841","name":"Xinxiang Medical University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100011841","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","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>Enterovirus 71 (EV71) is a primary etiological agent of hand-foot-mouth disease (HFMD) in children under 5\u202fyears of age and can cause severe neurological disorders even death. Therefore, elucidating the infection mechanism and pathogenicity of EV71 is essential for developing more effective and targeted therapies to prevent and control EV71-associated diseases. Here, we initially reported that the SUMO E3 ligase CBX4 is important for EV71 replication. Furthermore, we found that CBX4 interacts with the EV71 3D polymerase, and overexpression of CBX4 significantly extends the half-life of 3D, whereas knockdown of CBX4 reduces the stability of 3D protein. Subsequent investigations demonstrated that CBX4 mediates both SUMOylation and ubiquitination modifications of 3D, and treatment with protein SUMOylation inhibitor 2-D08 remarkably depresses EV71 replication and the expression of ectopically transfected 3D. The regulatory role of CBX4 and the effect of 2-D08 were also observed in other enteroviruses, including coxsackievirus B3 (CVB3) and poliovirus 1 (PV1). These findings revealed that CBX4 facilitates EV71 infection through inducing SUMOylation and stabilization of 3D polymerase, hinting its potential as a novel target for antiviral development.<\/jats:p>","DOI":"10.3389\/fmicb.2026.1775950","type":"journal-article","created":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T07:01:47Z","timestamp":1772607707000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["CBX4 facilitates EV71 replication by SUMOylation and stabilizing 3D polymerase"],"prefix":"10.3389","volume":"17","author":[{"given":"Rui","family":"Su","sequence":"first","affiliation":[{"name":"Department of Immunology, School of Basic Medical Sciences, Henan Medical University","place":["Xinxiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifan","family":"Niu","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Basic Medical Sciences, Henan Medical University","place":["Xinxiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aiping","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Basic Medical Sciences, Henan Medical University","place":["Xinxiang, China"]},{"name":"Xinxiang Engineering Technology Research Center of Immune Checkpoint Drug for Liver-Intestinal Tumors, Henan Medical University","place":["Xinxiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiesuo","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Basic Medical Sciences, Henan Medical University","place":["Xinxiang, China"]},{"name":"Xinxiang Engineering Technology Research Center of Immune Checkpoint Drug for Liver-Intestinal Tumors, Henan Medical University","place":["Xinxiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Wang","sequence":"additional","affiliation":[{"name":"Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Medical Technology, Henan Medical University","place":["Xinxiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,4]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1080\/22221751.2021.1906754","article-title":"Viral determinants that drive enterovirus-A71 fitness and virulence","volume":"10","author":"Ang","year":"2021","journal-title":"Emerg. Microbes Infect."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"31373","DOI":"10.1074\/jbc.M111.254896","article-title":"Sumoylation-promoted enterovirus 71 3C degradation correlates with a reduction in viral replication and cell apoptosis","volume":"286","author":"Chen","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1038\/s41392-023-01623-0","article-title":"CBX4 deletion promotes tumorigenesis under Kras(G12D) background by inducing genomic instability","volume":"8","author":"Chen","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"e0117324","DOI":"10.1128\/jvi.01173-24","article-title":"Tannic acid reactivates HIV-1 latency by mediating CBX4 degradation","volume":"99","author":"Chen","year":"2025","journal-title":"J. Virol."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"e2104126","DOI":"10.1002\/advs.202104126","article-title":"SUMOylation in viral replication and antiviral defense","volume":"9","author":"Fan","year":"2022","journal-title":"Adv. Sci."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1128\/jvi.02170-14","article-title":"Interaction of NS2 with AIMP2 facilitates the switch from ubiquitination to SUMOylation of M1 in influenza a virus-infected cells","volume":"89","author":"Gao","year":"2015","journal-title":"J. Virol."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"101136","DOI":"10.1016\/j.drup.2024.101136","article-title":"CBX4 counteracts cellular senescence to desensitize gastric cancer cells to chemotherapy by inducing YAP1 SUMOylation","volume":"77","author":"Gu","year":"2024","journal-title":"Drug Resist. Updates"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"9379","DOI":"10.1128\/jvi.00509-14","article-title":"Sumoylation of influenza a virus nucleoprotein is essential for intracellular trafficking and virus growth","volume":"88","author":"Han","year":"2014","journal-title":"J. Virol."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"4534","DOI":"10.1242\/jcs.193698","article-title":"SIRT1 inhibits EV71 genome replication and RNA translation by interfering with the viral polymerase and 5'UTR RNA","volume":"129","author":"Han","year":"2016","journal-title":"J. Cell Sci."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1093\/nar\/gky1007","article-title":"N6-methyladenosine modification and METTL3 modulate enterovirus 71 replication","volume":"47","author":"Hao","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/j.coviro.2014.03.007","article-title":"Update on enterovirus 71 infection","volume":"5","author":"Huang","year":"2014","journal-title":"Curr. Opin. Virol."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1007\/s13365-021-00995-9","article-title":"Viruses, SUMO, and immunity: the interplay between viruses and the host SUMOylation system","volume":"27","author":"Imbert","year":"2021","journal-title":"J. Neurovirol."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"102692","DOI":"10.1016\/j.ebiom.2020.102692","article-title":"CBX4 transcriptionally suppresses KLF6 via interaction with HDAC1 to exert oncogenic activities in clear cell renal cell carcinoma","volume":"53","author":"Jiang","year":"2020","journal-title":"EBioMedicine"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1016\/j.bbagrm.2011.01.001","article-title":"Biochemical characterization of enterovirus 71 3D RNA polymerase","volume":"1809","author":"Jiang","year":"2011","journal-title":"Biochim. Biophys. Acta Gene Regul. Mech."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"155","DOI":"10.3390\/v10040155","article-title":"Antiviral and inflammatory cellular signaling associated with enterovirus 71 infection","volume":"10","author":"Jin","year":"2018","journal-title":"Viruses"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"1094","DOI":"10.1016\/j.bmcl.2014.01.010","article-title":"Synthesis of 2\u2032,3\u2032,4\u2032-trihydroxyflavone (2-D08), an inhibitor of protein sumoylation","volume":"24","author":"Kim","year":"2014","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"395","DOI":"10.3345\/kjp.2016.59.10.395","article-title":"Enterovirus 71 infection and neurological complications","volume":"59","author":"Lee","year":"2016","journal-title":"Korean J. Pediatr."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"e1010801","DOI":"10.1371\/journal.ppat.1010801","article-title":"PRC1-independent binding and activity of RYBP on the KSHV genome during de novo infection","volume":"18","author":"Lee","year":"2022","journal-title":"PLoS Pathog."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"e1009336","DOI":"10.1371\/journal.ppat.1009336","article-title":"Viral RNA-binding ability conferred by SUMOylation at PB1 K612 of influenza a virus is essential for viral pathogenesis and transmission","volume":"17","author":"Li","year":"2021","journal-title":"PLoS Pathog."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1016\/j.ccr.2013.12.008","article-title":"Cbx4 governs HIF-1\u03b1 to potentiate angiogenesis of hepatocellular carcinoma by its SUMO E3 ligase activity","volume":"25","author":"Li","year":"2014","journal-title":"Cancer Cell"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"648","DOI":"10.1165\/rcmb.2021-0301OC","article-title":"CBX4 regulates long-form thymic stromal lymphopoietin-mediated airway inflammation through SUMOylation in house dust mite-induced asthma","volume":"66","author":"Liang","year":"2022","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1002\/rmv.1827","article-title":"Comparative epidemiology and virology of fatal and nonfatal cases of hand, foot and mouth disease in mainland China from 2008 to 2014","volume":"25","author":"Liu","year":"2015","journal-title":"Rev. Med. Virol."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"10472","DOI":"10.1128\/jvi.01756-16","article-title":"SUMO modification stabilizes enterovirus 71 polymerase 3D to facilitate viral replication","volume":"90","author":"Liu","year":"2016","journal-title":"J. Virol."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1016\/j.stem.2011.07.013","article-title":"Regulation of human epidermal stem cell proliferation and senescence requires polycomb- dependent and -independent functions of Cbx4","volume":"9","author":"Luis","year":"2011","journal-title":"Cell Stem Cell"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.stem.2011.12.006","article-title":"Nonoverlapping functions of the Polycomb group Cbx family of proteins in embryonic stem cells","volume":"10","author":"Morey","year":"2012","journal-title":"Cell Stem Cell"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"3643","DOI":"10.1016\/j.celrep.2019.02.088","article-title":"Maintenance of nucleolar homeostasis by CBX4 alleviates senescence and osteoarthritis","volume":"26","author":"Ren","year":"2019","journal-title":"Cell Rep."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"5602","DOI":"10.1128\/jvi.02063-12","article-title":"SUMOylation affects the interferon blocking activity of the influenza a nonstructural protein NS1 without affecting its stability or cellular localization","volume":"87","author":"Santos","year":"2013","journal-title":"J. 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Virol."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"2190","DOI":"10.3390\/v14102190","article-title":"Activation of host cellular signaling and mechanism of enterovirus 71 viral proteins associated with hand, foot and mouth disease","volume":"14","author":"Swain","year":"2022","journal-title":"Viruses"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"4529","DOI":"10.3390\/v7082832","article-title":"Replication and inhibitors of enteroviruses and parechoviruses","volume":"7","author":"van der Linden","year":"2015","journal-title":"Viruses"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"115659","DOI":"10.1016\/j.bone.2020.115659","article-title":"Biological functions of chromobox (CBX) proteins in stem cell self-renewal, lineage-commitment, cancer and development","volume":"143","author":"van Wijnen","year":"2021","journal-title":"Bone"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"e202303108","DOI":"10.1083\/jcb.202303108","article-title":"Inhibition of lysosome-tethered Ragulator-rag-3D complex restricts the replication of enterovirus 71 and Coxsackie A16","volume":"222","author":"Wang","year":"2023","journal-title":"J. Cell Biol."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"1141","DOI":"10.1038\/s41467-020-14870-4","article-title":"Targeting the CK1\u03b1\/CBX4 axis for metastasis in osteosarcoma","volume":"11","author":"Wang","year":"2020","journal-title":"Nat. Commun."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"e1010446","DOI":"10.1371\/journal.ppat.1010446","article-title":"PIAS1-mediated SUMOylation of influenza a virus PB2 restricts viral replication and virulence","volume":"18","author":"Wang","year":"2022","journal-title":"PLoS Pathog."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"e0059822","DOI":"10.1128\/jvi.00598-22","article-title":"Neddylation of enterovirus 71 VP2 protein reduces its stability and restricts viral replication","volume":"96","author":"Wang","year":"2022","journal-title":"J. Virol."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"e53855","DOI":"10.15252\/embr.202153855","article-title":"CBX4 contributes to HIV-1 latency by forming phase-separated nuclear bodies and SUMOylating EZH2","volume":"23","author":"Wu","year":"2022","journal-title":"EMBO Rep."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"4","DOI":"10.7774\/cevr.2017.6.1.4","article-title":"Enterovirus 71 infection and vaccines","volume":"6","author":"Yi","year":"2017","journal-title":"Clin. Exp. Vaccine Res."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"286","DOI":"10.3389\/fmicb.2018.00286","article-title":"Enterovirus A71 proteins: structure and function","volume":"9","author":"Yuan","year":"2018","journal-title":"Front. Microbiol."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"e0078623","DOI":"10.1128\/jvi.00786-23","article-title":"Ubiquitin E3 ligase SPOP is a host negative regulator of enterovirus 71-encoded 2A protease","volume":"97","author":"Zang","year":"2023","journal-title":"J. Virol."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"1387","DOI":"10.1007\/s12250-021-00417-4","article-title":"ANXA2 facilitates enterovirus 71 infection by interacting with 3D polymerase and PI4KB to assist the assembly of replication organelles","volume":"36","author":"Zhang","year":"2021","journal-title":"Virol. Sin."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1038\/s41419-024-06745-z","article-title":"CBX4 plays a bidirectional role in transcriptional regulation and lung adenocarcinoma progression","volume":"15","author":"Zhao","year":"2024","journal-title":"Cell Death Dis."}],"updated-by":[{"DOI":"10.3389\/fmicb.2026.1835255","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T00:00:00Z","timestamp":1776038400000}}],"container-title":["Frontiers in Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2026.1775950\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T21:16:14Z","timestamp":1776114974000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2026.1775950\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,4]]},"references-count":46,"alternative-id":["10.3389\/fmicb.2026.1775950"],"URL":"https:\/\/doi.org\/10.3389\/fmicb.2026.1775950","relation":{},"ISSN":["1664-302X"],"issn-type":[{"value":"1664-302X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,4]]},"article-number":"1775950"}}