{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T18:57:43Z","timestamp":1791485863194,"version":"4.3.4"},"update-to":[{"DOI":"10.1371\/journal.ppat.1014653","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:00:00Z","timestamp":1791417600000}}],"reference-count":37,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:00:00Z","timestamp":1791158400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Key Research and Development Program of China","award":["2023YFD1801800"],"award-info":[{"award-number":["2023YFD1801800"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32172829"],"award-info":[{"award-number":["32172829"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32072848"],"award-info":[{"award-number":["32072848"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Beijing Municipal Natural Science Foundation","award":["6232026"],"award-info":[{"award-number":["6232026"]}]},{"DOI":"10.13039\/501100013909","name":"State Key Laboratory of Veterinary Biotechnology","doi-asserted-by":"publisher","award":["2025SKLVPHS07"],"award-info":[{"award-number":["2025SKLVPHS07"]}],"id":[{"id":"10.13039\/501100013909","id-type":"DOI","asserted-by":"publisher"}]},{"name":"2115 Talent Development Program of China Agricultural University","id":[{"id":"https:\/\/ror.org\/04v3ywz14","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Pseudorabies virus (PRV), an alphaherpesvirus, establishes lifelong latency in neurons and requires efficient reactivation for pathogenesis. Thymidine kinase (TK), encoded by UL23, is a key virulence factor essential for viral replication in non-dividing cells and for reactivation from latency; however, the regulatory mechanisms governing TK function remain poorly defined. Here, we identify TK as a substrate for small ubiquitin-like modifier (SUMO) modification and investigate its functional significance during PRV infection. We show that TK undergoes endogenous SUMOylation during viral infection is conjugated by SUMO-1, SUMO-2, and SUMO-3, with lysine residues K242 and K267 serving as the principal SUMO acceptor sites. Disruption of these SUMOylation sites does not affect TK stability and kinase activity but markedly alters its subcellular localization by reducing nuclear accumulation. Functionally, SUMOylation of TK is dispensable for viral replication in epithelial PK15 cells but facilitates efficient replication in neuronal N2a cells. Using an\n                    <jats:italic>in vitro<\/jats:italic>\n                    latency\/reactivation model, we further show that SUMOylation-deficient TK does not affect the establishment of latent infection but markedly impairs viral reactivation and subsequent productive replication. In a mouse infection model, disruption of TK SUMOylation attenuates PRV pathogenicity, accompanied by reduced viral loads in the brain and milder histopathological lesions. Collectively, our findings demonstrate that SUMOylation regulates nuclear localization and biological function of PRV TK, thereby facilitating efficient neuronal replication, viral reactivation, and pathogenesis. These findings provide new insights into the post-translational regulation of alphaherpesvirus TK and identify TK SUMOylation as a potential target for controlling PRV infection.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1014653","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T17:59:07Z","timestamp":1791223147000},"page":"e1014653","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["SUMOylation of pseudorabies virus thymidine kinase regulates its nuclear localization and facilitates neuronal replication and reactivation"],"prefix":"10.1371","volume":"22","author":[{"given":"Xuan","family":"Chen","sequence":"first","affiliation":[{"name":"State Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University","place":["Beijing, China"]},{"name":"College of Veterinary Medicine, China Agricultural University","place":["Beijing, China"],"department":["Department of Basic Veterinary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuang","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University","place":["Beijing, China"]},{"name":"College of Veterinary Medicine, China Agricultural University","place":["Beijing, China"],"department":["Department of Basic Veterinary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongyue","family":"Xing","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University","place":["Beijing, China"]},{"name":"College of Veterinary Medicine, China Agricultural University","place":["Beijing, China"],"department":["Department of Basic Veterinary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Song","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University","place":["Beijing, China"]},{"name":"College of Veterinary Medicine, China Agricultural University","place":["Beijing, China"],"department":["Department of Basic Veterinary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University","place":["Beijing, China"]},{"name":"College of Veterinary Medicine, China Agricultural University","place":["Beijing, China"],"department":["Department of Basic Veterinary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxin","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University","place":["Beijing, China"]},{"name":"College of Veterinary Medicine, China Agricultural University","place":["Beijing, China"],"department":["Department of Basic Veterinary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Huang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University","place":["Beijing, China"]},{"name":"College of Veterinary Medicine, China Agricultural University","place":["Beijing, China"],"department":["Department of Basic Veterinary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Kuang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University","place":["Beijing, China"]},{"name":"College of Veterinary Medicine, China Agricultural University","place":["Beijing, China"],"department":["Department of Basic Veterinary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xian","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University","place":["Beijing, China"]},{"name":"College of Veterinary Medicine, China Agricultural University","place":["Beijing, China"],"department":["Department of Basic Veterinary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinlei","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University","place":["Beijing, China"]},{"name":"College of Veterinary Medicine, China Agricultural University","place":["Beijing, China"],"department":["Department of Basic Veterinary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqi","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University","place":["Beijing, China"]},{"name":"College of Veterinary Medicine, China Agricultural University","place":["Beijing, China"],"department":["Department of Basic Veterinary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nianzhi","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University","place":["Beijing, China"]},{"name":"College of Veterinary Medicine, China Agricultural University","place":["Beijing, China"],"department":["Department of Preventive Veterinary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rulan","family":"Bai","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University","place":["Beijing, China"]},{"name":"College of Veterinary Medicine, China Agricultural University","place":["Beijing, China"],"department":["Department of Basic Veterinary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changyong","family":"Cheng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Applied Biotechnology on Animal Science & Veterinary Medicine of Zhejiang Province, College of Veterinary Medicine of Zhejiang A&F University","place":["Hangzhou, Zhejiang Province, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Yuan","sequence":"additional","affiliation":[{"name":"Ministry of Education Key Laboratory for Animal Pathogens and Biosafety, College of Veterinary Medicine, Henan Agricultural University","place":["Zhengzhou, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Tang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University","place":["Beijing, China"]},{"name":"College of Veterinary Medicine, China Agricultural University","place":["Beijing, China"],"department":["Department of Basic Veterinary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9015-0819","authenticated-orcid":true,"given":"Rui","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University","place":["Beijing, China"]},{"name":"College of Veterinary Medicine, China Agricultural University","place":["Beijing, China"],"department":["Department of Basic Veterinary"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,10,5]]},"reference":[{"issue":"1","key":"ppat.1014653.ref001","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1007\/s11262-024-02122-2","article-title":"Pseudorabies virus as a zoonosis: scientific and public health implications","volume":"61","author":"Y Chen","year":"2025","journal-title":"Virus Genes"},{"issue":"3","key":"ppat.1014653.ref002","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1128\/MMBR.69.3.462-500.2005","article-title":"Molecular biology of pseudorabies virus: impact on neurovirology and veterinary medicine","volume":"69","author":"LE Pomeranz","year":"2005","journal-title":"Microbiol Mol Biol Rev"},{"issue":"4","key":"ppat.1014653.ref003","doi-asserted-by":"crossref","first-page":"427","DOI":"10.15252\/embj.201490843","article-title":"KSHV-TK: thymidine kinase or tyrosine kinase?","volume":"34","author":"M Lagunoff","year":"2015","journal-title":"EMBO J"},{"key":"ppat.1014653.ref004","doi-asserted-by":"crossref","first-page":"941","DOI":"10.3389\/fmicb.2019.00941","article-title":"Alpha-Herpesvirus Thymidine Kinase Genes Mediate Viral Virulence and Are Potential Therapeutic Targets","volume":"10","author":"Y Xie","year":"2019","journal-title":"Front Microbiol"},{"issue":"5","key":"ppat.1014653.ref005","first-page":"599","article-title":"HSV-1 thymidine kinase promotes virulence and latency in the mouse","volume":"24","author":"YJ Gordon","year":"1983","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"12","key":"ppat.1014653.ref006","doi-asserted-by":"crossref","first-page":"4736","DOI":"10.1073\/pnas.86.12.4736","article-title":"Thymidine kinase-negative herpes simplex virus mutants establish latency in mouse trigeminal ganglia but do not reactivate","volume":"86","author":"DM Coen","year":"1989","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"2","key":"ppat.1014653.ref007","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1159\/000150188","article-title":"Role of herpes simplex virus thymidine kinase expression in viral pathogenesis and latency","volume":"32","author":"RB Tenser","year":"1991","journal-title":"Intervirology"},{"issue":"10","key":"ppat.1014653.ref008","first-page":"753","article-title":"A study of the ability of a TK-negative and gI\/gE-negative pseudorabies virus (PRV) mutant inoculated by different routes to protect pigs against PRV infection","volume":"47","author":"M Ferrari","year":"2000","journal-title":"J Vet Med B Infect Dis Vet Public Health"},{"key":"ppat.1014653.ref009","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1007\/BF01317195","article-title":"Latency of a thymidine kinase-negative pseudorabies vaccine virus detected by the polymerase chain reaction","volume":"122","author":"DM Volz","year":"1992","journal-title":"Arch Virol"},{"issue":"7","key":"ppat.1014653.ref010","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1007176","article-title":"A genome-wide screen of Epstein-Barr virus proteins that modulate host SUMOylation identifies a SUMO E3 ligase conserved in herpesviruses","volume":"14","author":"CF De La Cruz-Herrera","year":"2018","journal-title":"PLoS Pathog"},{"issue":"7","key":"ppat.1014653.ref011","article-title":"SUMOylation in 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pathogenesis and transmission","volume":"17","author":"J Li","year":"2021","journal-title":"PLoS Pathog"},{"issue":"19","key":"ppat.1014653.ref015","doi-asserted-by":"crossref","DOI":"10.1128\/JVI.01086-20","article-title":"NS5 Sumoylation Directs Nuclear Responses That Permit Zika Virus To Persistently Infect Human Brain Microvascular Endothelial Cells","volume":"94","author":"JN Conde","year":"2020","journal-title":"J Virol"},{"key":"ppat.1014653.ref016","doi-asserted-by":"crossref","first-page":"197962","DOI":"10.1016\/j.virusres.2020.197962","article-title":"Role of SUMOylation in Human Oncogenic Herpesvirus Infection","volume":"283","author":"Y Zhang","year":"2020","journal-title":"Virus Res"},{"issue":"9","key":"ppat.1014653.ref017","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1002245","article-title":"A viral ubiquitin ligase has substrate preferential SUMO targeted ubiquitin ligase activity that counteracts intrinsic antiviral defence","volume":"7","author":"C Boutell","year":"2011","journal-title":"PLoS Pathog"},{"issue":"15","key":"ppat.1014653.ref018","doi-asserted-by":"crossref","first-page":"9912","DOI":"10.1128\/JVI.79.15.9912-9925.2005","article-title":"Kaposi\u2019s sarcoma-associated herpesvirus K-bZIP represses gene transcription via SUMO modification","volume":"79","author":"Y Izumiya","year":"2005","journal-title":"J Virol"},{"issue":"9","key":"ppat.1014653.ref019","doi-asserted-by":"crossref","first-page":"4383","DOI":"10.1128\/JVI.02369-09","article-title":"Sumoylation of the Epstein-Barr virus BZLF1 protein inhibits its transcriptional activity and is regulated by the virus-encoded protein kinase","volume":"84","author":"SR Hagemeier","year":"2010","journal-title":"J Virol"},{"issue":"5","key":"ppat.1014653.ref020","doi-asserted-by":"crossref","first-page":"2388","DOI":"10.1128\/JVI.75.5.2388-2399.2001","article-title":"Epstein-barr virus immediate-early protein BZLF1 is SUMO-1 modified and disrupts promyelocytic leukemia bodies","volume":"75","author":"AL Adamson","year":"2001","journal-title":"J Virol"},{"key":"ppat.1014653.ref021","first-page":"962","article-title":"Human Oncogenic Herpesvirus and Post-translational Modifications - Phosphorylation and SUMOylation","volume":"7","author":"P-C Chang","year":"2016","journal-title":"Front Microbiol"},{"issue":"4","key":"ppat.1014653.ref022","doi-asserted-by":"crossref","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":"F Imbert","year":"2021","journal-title":"J Neurovirol"},{"key":"ppat.1014653.ref023","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1007\/978-3-319-50044-7_21","article-title":"Viral Interplay with the Host Sumoylation System","volume":"963","author":"VG Wilson","year":"2017","journal-title":"Adv Exp Med Biol"},{"key":"ppat.1014653.ref024","doi-asserted-by":"crossref","first-page":"31","DOI":"10.3389\/fmicb.2012.00031","article-title":"Post-Translational Modifications of Kaposi\u2019s Sarcoma-Associated Herpesvirus Regulatory Proteins - SUMO and KSHV","volume":"3","author":"M Campbell","year":"2012","journal-title":"Front Microbiol"},{"issue":"6","key":"ppat.1014653.ref025","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1034\/j.1600-0854.2002.30601.x","article-title":"Ubiquitin-related modifier SUMO1 and nucleocytoplasmic transport","volume":"3","author":"A Pichler","year":"2002","journal-title":"Traffic"},{"key":"ppat.1014653.ref026","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1146\/annurev-biochem-061909-093311","article-title":"Sumoylation: a regulatory protein modification in health and disease","volume":"82","author":"A Flotho","year":"2013","journal-title":"Annu Rev 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of Pseudorabies Virus Latency and Reactivation and Identification of Key Viral Latency-Associated Genes","volume":"15","author":"L Pan","year":"2023","journal-title":"Viruses"}],"updated-by":[{"DOI":"10.1371\/journal.ppat.1014653","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:00:00Z","timestamp":1791417600000}}],"container-title":["PLOS Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1014653","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T17:56:02Z","timestamp":1791482162000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1014653"}},"subtitle":[],"editor":[{"given":"Pinghui","family":"Feng","sequence":"first","affiliation":[{"name":"University of Southern California","place":["UNITED STATES OF AMERICA"]}],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,10,5]]},"references-count":37,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,10,5]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.ppat.1014653","relation":{},"ISSN":["1553-7374"],"issn-type":[{"value":"1553-7374","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,5]]}}}