{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T06:48:46Z","timestamp":1784616526161,"version":"3.55.0"},"reference-count":52,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2020,12,4]],"date-time":"2020-12-04T00:00:00Z","timestamp":1607040000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["Grant-in-Aid for Scientific Research 18K06642"],"award-info":[{"award-number":["Grant-in-Aid for Scientific Research 18K06642"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Herpes simplex virus-1 (HSV-1) is the causative agent of cold sores, keratitis, meningitis, and encephalitis. HSV-1-encoded ICP5, the major capsid protein, is essential for capsid assembly during viral replication. Ubiquitination is a post-translational modification that plays a critical role in the regulation of cellular events such as proteasomal degradation, protein trafficking, and the antiviral response and viral events such as the establishment of infection and viral replication. Ub-activating enzyme (E1, also named UBE1) is involved in the first step in the ubiquitination. However, it is still unknown whether UBE1 contributes to viral infection or the cellular antiviral response. Here, we found that UBE1a suppressed HSV-1 replication and contributed to the antiviral response. The UBE1a inhibitor PYR-41 increased HSV-1 production. Immunofluorescence analysis revealed that UBE1a highly expressing cells presented low ICP5 expression, and vice versa. UBE1a inhibition by PYR-41 and shRNA increased ICP5 expression in HSV-1-infected cells. UBE1a reduced and retarded ICP5 protein expression, without affecting transcription of ICP5 mRNA or degradation of ICP5 protein. Additionally, UBE1a interacted with ICP27, and both partially co-localized at the Hsc70 foci\/virus-induced chaperone-enriched (VICE) domains. PYR-41 reduced the co-localization of UBE1a and ICP27. Thus, our findings provide insights into the mechanism of UBE1a in the cellular response to viral infection.<\/jats:p>","DOI":"10.3390\/v12121391","type":"journal-article","created":{"date-parts":[[2020,12,7]],"date-time":"2020-12-07T12:24:39Z","timestamp":1607343879000},"page":"1391","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["UBE1a Suppresses Herpes Simplex Virus-1 Replication"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0052-4336","authenticated-orcid":false,"given":"Marina","family":"Ikeda","sequence":"first","affiliation":[{"name":"Department of Cell Biology, Kyoto Pharmaceutical University, Kyoto 607-8412, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiro","family":"Ito","sequence":"additional","affiliation":[{"name":"Laboratory of Cell Signaling, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2861-603X","authenticated-orcid":false,"given":"Yuichi","family":"Sekine","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Kyoto Pharmaceutical University, Kyoto 607-8412, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5165-0789","authenticated-orcid":false,"given":"Masahiro","family":"Fujimuro","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Kyoto Pharmaceutical University, Kyoto 607-8412, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,4]]},"reference":[{"key":"ref_1","first-page":"2501","article-title":"Whitley, R.J. Herpes Simplex Viruses","volume":"Volume 2","author":"Knipe","year":"2007","journal-title":"Fields Virology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"262415","DOI":"10.1155\/2010\/262415","article-title":"Towards an Understanding of the Herpes Simplex Virus Type 1 Latency-Reactivation Cycle","volume":"2010","author":"Perng","year":"2010","journal-title":"Interdiscip. Perspect. Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1006\/viro.1996.0668","article-title":"The herpes simplex virus type 1 UL6 protein is essential for cleavage and packaging but not for genomic inversion","volume":"226","author":"Lamberti","year":"1996","journal-title":"Virology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1016\/0092-8674(84)90035-7","article-title":"The intranuclear location of a herpes simplex virus DNA-binding protein is determined by the status of viral DNA replication","volume":"36","author":"Quinlan","year":"1984","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"7175","DOI":"10.1128\/JVI.78.13.7175-7185.2004","article-title":"Nuclear sequestration of cellular chaperone and proteasomal machinery during herpes simplex virus type 1 infection","volume":"78","author":"Burch","year":"2004","journal-title":"J. Virol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"10740","DOI":"10.1128\/JVI.79.16.10740-10749.2005","article-title":"Herpes simplex virus type 1 DNA polymerase requires the mammalian chaperone hsp90 for proper localization to the nucleus","volume":"79","author":"Burch","year":"2005","journal-title":"J. Virol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2695","DOI":"10.1242\/jcs.02981","article-title":"Herpes simplex virus type I disrupts the ATR-dependent DNA-damage response during lytic infection","volume":"119","author":"Wilkinson","year":"2006","journal-title":"J. Cell Sci."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Livingston, C.M., Ifrim, M.F., Cowan, A.E., and Weller, S.K. (2009). Virus-Induced Chaperone-Enriched (VICE) Domains Function as Nuclear Protein Quality Control Centers during HSV-1 Infection. PLoS Pathog., 5.","DOI":"10.1371\/journal.ppat.1000619"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"6324","DOI":"10.1128\/JVI.00455-08","article-title":"Oligomerization of ICP4 and Rearrangement of Heat Shock Proteins May Be Important for Herpes Simplex Virus Type 1 Prereplicative Site Formation","volume":"82","author":"Livingston","year":"2008","journal-title":"J. Virol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1016\/j.sbi.2011.09.009","article-title":"Reading the ubiquitin postal. code","volume":"21","author":"Trempe","year":"2011","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1038\/35056563","article-title":"Themes and variations on ubiquitylation","volume":"2","author":"Weissman","year":"2001","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1016\/j.tcb.2013.12.003","article-title":"Perilous journey: A tour of the ubiquitin-proteasome system","volume":"24","author":"Kleiger","year":"2014","journal-title":"Trends Cell Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1146\/annurev.biochem.70.1.503","article-title":"Mechanisms Underlying Ubiquitination","volume":"70","author":"Pickart","year":"2001","journal-title":"Annu. Rev. Biochem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2543","DOI":"10.1016\/S0021-9258(18)34958-5","article-title":"Ubiquitin-activating enzyme. Mechanism and role in protein-ubiquitin conjugation","volume":"257","author":"Haas","year":"1982","journal-title":"J. Biol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1038\/35056583","article-title":"Protein regulation by monoubiquitin","volume":"2","author":"Hicke","year":"2001","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1002\/j.1460-2075.1991.tb07940.x","article-title":"UBA 1: An essential yeast gene encoding ubiquitin-activating enzyme","volume":"10","author":"McGrath","year":"1991","journal-title":"EMBO J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"15608","DOI":"10.1074\/jbc.271.26.15608","article-title":"The ubiquitin-activating enzyme E1 is phosphorylated and localized to the nucleus in a cell cycle-dependent manner","volume":"271","author":"Stephen","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1016\/j.molmed.2015.08.003","article-title":"UBA1: At the Crossroads of Ubiquitin Homeostasis and Neurodegeneration","volume":"21","author":"Groen","year":"2015","journal-title":"Trends Mol. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"10895","DOI":"10.1074\/jbc.272.16.10895","article-title":"Identification of a region within the ubiquitin-activating enzyme required for nuclear targeting and phosphorylation","volume":"272","author":"Stephen","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1128\/JVI.76.2.841-850.2002","article-title":"Herpes simplex virus type 1 immediate-early protein ICP0 and its isolated RING finger domain act as ubiquitin E3 ligases in vitro","volume":"76","author":"Boutell","year":"2002","journal-title":"J. Virol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"36596","DOI":"10.1074\/jbc.M300776200","article-title":"The Herpes Simplex Virus Type 1 (HSV-1) Regulatory Protein ICP0 Interacts with and Ubiquitinates p53","volume":"278","author":"Boutell","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1099\/vir.0.048900-0","article-title":"Regulation of alphaherpesvirus infections by the ICP0 family of proteins","volume":"94","author":"Boutell","year":"2013","journal-title":"J. Gen. Virol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.ab.2011.06.034","article-title":"A spectrophotometric assay for conjugation of ubiquitin and ubiquitin-like proteins","volume":"418","author":"Berndsen","year":"2011","journal-title":"Anal. Biochem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1038\/s41598-017-00401-7","article-title":"Kaposi\u2019s sarcoma-associated herpesvirus ORF34 is essential for late gene expression and virus production","volume":"7","author":"Nishimura","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.1101\/gad.1935210","article-title":"Ronin\/Hcf-1 binds to a hyperconserved enhancer element and regulates genes involved in the growth of embryonic stem cells","volume":"24","author":"Dejosez","year":"2010","journal-title":"Genes Dev."},{"key":"ref_26","first-page":"502","article-title":"Arctigenin induces the apoptosis of primary effusion lymphoma cells under conditions of glucose deprivation","volume":"52","author":"Baba","year":"2018","journal-title":"Int. J. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"293","DOI":"10.3892\/ijo.2015.3247","article-title":"Diallyl trisulfide induces apoptosis by suppressing NF-B signaling through destabilization of TRAF6 in primary effusion lymphoma","volume":"48","author":"Shigemi","year":"2016","journal-title":"Int. J. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/0014-5793(94)00647-4","article-title":"Production and characterization of monoclonal antibodies specific to multi-ubiquitin chains of polyubiquitinated proteins","volume":"349","author":"Fujimuro","year":"1994","journal-title":"FEBS Lett."},{"key":"ref_29","first-page":"2745","article-title":"High-efficiency transformation of mammalian cells by plasmid DNA","volume":"7","author":"Chen","year":"1987","journal-title":"Mol. Cell. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Watanabe, T., Nishimura, M., Izumi, T., Kuriyama, K., Iwaisako, Y., Hosokawa, K., Takaori-Kondo, A., and Fujimuro, M. (2019). Kaposi\u2019s Sarcoma-Associated Herpesvirus ORF66 Is Essential for Late Gene Expression and Virus Production via Interaction with ORF34. J. Virol., 94.","DOI":"10.1101\/728147"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1111\/j.1432-1033.1997.00427.x","article-title":"Dynamics of ubiquitin conjugation during heat-shock response revealed by using a monoclonal antibody specific to multi-ubiquitin chains","volume":"249","author":"Fujimuro","year":"1997","journal-title":"Eur. J. Biochem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"9472","DOI":"10.1158\/0008-5472.CAN-07-0568","article-title":"Inhibitors of ubiquitin-activating enzyme (E1), a new class of potential cancer therapeutics","volume":"67","author":"Yang","year":"2007","journal-title":"Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1042\/bj3000701","article-title":"Nuclear localization of the ubiquitin-activating enzyme, E1, is cell-cycle-dependent","volume":"300","author":"Grenfell","year":"1994","journal-title":"Biochem. J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3538","DOI":"10.1128\/JVI.02395-07","article-title":"Herpes Simplex Virus ICP27 Increases Translation of a Subset of Viral Late mRNAs","volume":"82","author":"Knipe","year":"2008","journal-title":"J. Virol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4124","DOI":"10.1128\/JVI.02319-09","article-title":"Herpes simplex virus 1 regulatory protein ICP27 undergoes a head-to-tail intramolecular interaction","volume":"84","author":"Hernandez","year":"2010","journal-title":"J. Virol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5309","DOI":"10.1128\/JVI.00238-09","article-title":"Arginine Methylation of the ICP27 RGG Box Regulates ICP27 Export and Is Required for Efficient Herpes Simplex Virus 1 Replication","volume":"83","author":"Souki","year":"2009","journal-title":"J. Virol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"8970","DOI":"10.1128\/JVI.00801-09","article-title":"Arginine Methylation of the ICP27 RGG Box Regulates the Functional Interactions of ICP27 with SRPK1 and Aly\/REF during Herpes Simplex Virus 1 Infection","volume":"83","author":"Souki","year":"2009","journal-title":"J. Virol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2770","DOI":"10.1128\/JVI.74.6.2770-2776.2000","article-title":"The Kinetics of VP5 mRNA Expression Is Not Critical for Viral Replication in Cultured Cells","volume":"74","author":"Lieu","year":"2000","journal-title":"J. Virol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Jin, F., Li, S., Zheng, K., Zhuo, C., Ma, K., Chen, M., Wang, Q., Zhang, P., Fan, J., and Ren, Z. (2014). Silencing herpes simplex virus type 1 capsid protein encoding genes by siRNA: A promising antiviral therapeutic approach. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0096623"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Montellese, C., van den Heuvel, J., Ashiono, C., D\u00f6rner, K., Melnik, A., Jonas, S., Zemp, I., Picotti, P., Gillet, L.C., and Kutay, U. (2020). USP16 counteracts mono-ubiquitination of RPS27a and promotes maturation of the 40S ribosomal subunit. Elife, 9.","DOI":"10.7554\/eLife.54435"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Jung, Y., Kim, H.D., Yang, H.W., Kim, H.J., Jang, C.Y., and Kim, J. (2017). Modulating cellular balance of Rps3 mono-ubiquitination by both Hel2 E3 ligase and Ubp3 deubiquitinase regulates protein quality control. Exp. Mol. Med., 49.","DOI":"10.1038\/emm.2017.128"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1038\/s41580-019-0118-2","article-title":"Mechanisms and functions of ribosome-associated protein quality control","volume":"20","author":"Joazeiro","year":"2019","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2200","DOI":"10.1128\/JVI.00917-09","article-title":"ICP27 Phosphorylation Site Mutants Are Defective in Herpes Simplex Virus 1 Replication and Gene Expression","volume":"84","author":"Rojas","year":"2010","journal-title":"J. Virol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2212","DOI":"10.1128\/JVI.01388-09","article-title":"ICP27 Phosphorylation Site Mutants Display Altered Functional Interactions with Cellular Export Factors Aly\/REF and TAP\/NXF1 but Are Able To Bind Herpes Simplex Virus 1 RNA","volume":"84","author":"Rojas","year":"2010","journal-title":"J. Virol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"12818","DOI":"10.1073\/pnas.1512559112","article-title":"Dynamic ubiquitination drives herpesvirus neuroinvasion","volume":"112","author":"Huffmaster","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"6555","DOI":"10.1128\/JVI.00295-12","article-title":"Herpes Simplex Virus Glycoproteins gH\/gL and gB Bind Toll-Like Receptor 2, and Soluble gH\/gL Is Sufficient To activate NF-\u03baB","volume":"86","author":"Leoni","year":"2012","journal-title":"J. Virol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"36059","DOI":"10.1074\/jbc.M306198200","article-title":"Protection by herpes simplex virus glycoprotein D against Fas-mediated apoptosis: Role of nuclear factor \u03baB","volume":"278","author":"Medici","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1146\/annurev.biochem.78.070907.102750","article-title":"The Role of Ubiquitin in NF-\u03baB Regulatory Pathways","volume":"78","author":"Skaug","year":"2009","journal-title":"Annu. Rev. Biochem."},{"key":"ref_49","first-page":"38","article-title":"Evasion of host antiviral innate immunity by HSV-1, an update","volume":"13","author":"Su","year":"2016","journal-title":"Virol. J. BioMed Cent."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"8815","DOI":"10.1073\/pnas.161283098","article-title":"The infected cell protein 0 of herpes simplex virus 1 dynamically interacts with proteasomes, binds and activates the cdc34 E2 ubiquitin-conjugating enzyme, and possesses in vitro E3 ubiquitin ligase activity","volume":"98","author":"Hagglund","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"8963","DOI":"10.1073\/pnas.1533420100","article-title":"The degradation of promyelocytic leukemia and Sp100 proteins by herpes simplex virus 1 is mediated by the ubiquitin-conjugating enzyme UbcH5a","volume":"100","author":"Gu","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1093\/emboj\/16.7.1519","article-title":"A novel ubiquitin-specific protease is dynamically associated with the PML nuclear domain and binds to a herpesvirus regulatory protein","volume":"16","author":"Everett","year":"1997","journal-title":"EMBO J."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/12\/12\/1391\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:41:46Z","timestamp":1760179306000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/12\/12\/1391"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,4]]},"references-count":52,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["v12121391"],"URL":"https:\/\/doi.org\/10.3390\/v12121391","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,4]]}}}