{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T23:29:27Z","timestamp":1792106967272,"version":"4.4.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1010045","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,11,18]],"date-time":"2021-11-18T00:00:00Z","timestamp":1637193600000}}],"reference-count":121,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2021,11,8]],"date-time":"2021-11-08T00:00:00Z","timestamp":1636329600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-CA232616-02"],"award-info":[{"award-number":["R01-CA232616-02"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 AI147060-01A1"],"award-info":[{"award-number":["R01 AI147060-01A1"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 CA229673-01A1"],"award-info":[{"award-number":["R01 CA229673-01A1"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P01 CA022443-42"],"award-info":[{"award-number":["P01 CA022443-42"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32AI078985"],"award-info":[{"award-number":["T32AI078985"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003802","name":"University Research Committee, University of Hong Kong","doi-asserted-by":"publisher","award":["GRF106170163"],"award-info":[{"award-number":["GRF106170163"]}],"id":[{"id":"10.13039\/501100003802","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003802","name":"University Research Committee, University of Hong Kong","doi-asserted-by":"publisher","award":["GRF17122420"],"award-info":[{"award-number":["GRF17122420"]}],"id":[{"id":"10.13039\/501100003802","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Epstein-Barr virus (EBV) is a human herpesvirus that causes infectious mononucleosis and contributes to both B-cell and epithelial-cell malignancies. EBV-infected epithelial cell tumors, including nasopharyngeal carcinoma (NPC), are largely composed of latently infected cells, but the mechanism(s) maintaining viral latency are poorly understood. Expression of the EBV BZLF1 (Z) and BRLF1 (R) encoded immediate-early (IE) proteins induces lytic infection, and these IE proteins activate each other\u2019s promoters. \u0394Np63\u03b1 (a p53 family member) is required for proliferation and survival of basal epithelial cells and is over-expressed in NPC tumors. Here we show that \u0394Np63\u03b1 promotes EBV latency by inhibiting activation of the BZLF1 IE promoter (Zp). Furthermore, we find that another p63 gene splice variant, TAp63\u03b1, which is expressed in some Burkitt and diffuse large B cell lymphomas, also represses EBV lytic reactivation. We demonstrate that \u0394Np63\u03b1 inhibits the Z promoter indirectly by preventing the ability of other transcription factors, including the viral IE R protein and the cellular KLF4 protein, to activate Zp. Mechanistically, we show that \u0394Np63\u03b1 promotes viral latency in undifferentiated epithelial cells both by enhancing expression of a known Zp repressor protein, c-myc, and by decreasing cellular p38 kinase activity. Furthermore, we find that the ability of cis-platinum chemotherapy to degrade \u0394Np63\u03b1 contributes to the lytic-inducing effect of this agent in EBV-infected epithelial cells. Together these findings demonstrate that the loss of \u0394Np63\u03b1 expression, in conjunction with enhanced expression of differentiation-dependent transcription factors such as BLIMP1 and KLF4, induces lytic EBV reactivation during normal epithelial cell differentiation. Conversely, expression of \u0394Np63\u03b1 in undifferentiated nasopharyngeal carcinoma cells and TAp63\u03b1 in Burkitt lymphoma promotes EBV latency in these malignancies.<\/jats:p>","DOI":"10.1371\/journal.ppat.1010045","type":"journal-article","created":{"date-parts":[[2021,11,8]],"date-time":"2021-11-08T18:37:03Z","timestamp":1636396623000},"page":"e1010045","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":16,"title":["\u0394Np63\u03b1 promotes Epstein-Barr virus latency in undifferentiated epithelial cells"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7967-6895","authenticated-orcid":true,"given":"Nicholas","family":"Van Sciver","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Ohashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dhananjay M.","family":"Nawandar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas P.","family":"Pauly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denis","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen R.","family":"Makielski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6109-8126","authenticated-orcid":true,"given":"Jillian A.","family":"Bristol","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sai Wah","family":"Tsao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul F.","family":"Lambert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric C.","family":"Johannsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shannon C.","family":"Kenney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,11,8]]},"reference":[{"key":"ppat.1010045.ref001","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/1750-9378-9-38","article-title":"Global burden of deaths from Epstein-Barr virus attributable malignancies 1990\u20132010","volume":"9","author":"G Khan","year":"2014","journal-title":"Infect Agent Cancer"},{"key":"ppat.1010045.ref002","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1038\/nrc.2016.92","article-title":"Epstein\u2013Barr virus: more than 50 years old and still providing surprises","volume":"16","author":"LS Young","year":"2016","journal-title":"Nat Rev Cancer"},{"key":"ppat.1010045.ref003","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1128\/JVI.79.2.1296-1307.2005","article-title":"Terminal Differentiation into Plasma Cells Initiates the Replicative Cycle of Epstein-Barr Virus In Vivo","volume":"79","author":"LL Laichalk","year":"2005","journal-title":"J Virol"},{"key":"ppat.1010045.ref004","doi-asserted-by":"crossref","first-page":"13566","DOI":"10.1128\/JVI.01055-07","article-title":"Plasma Cell-Specific Transcription Factor XBP-1s Binds to and Transactivates the Epstein-Barr Virus BZLF1 Promoter","volume":"81","author":"CC Sun","year":"2007","journal-title":"J Virol"},{"key":"ppat.1010045.ref005","doi-asserted-by":"crossref","first-page":"7363","DOI":"10.1128\/JVI.00154-07","article-title":"X-Box-Binding Protein 1 Activates Lytic Epstein-Barr Virus Gene Expression in Combination with Protein Kinase D.","volume":"81","author":"PM Bhende","year":"2007","journal-title":"J Virol"},{"key":"ppat.1010045.ref006","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1002\/ijc.2910330106","article-title":"Cross-linking of cell surface immunoglobulins induces epstein-barr virus in burkitt lymphoma lines","volume":"33","author":"K. Takada","year":"1984","journal-title":"Int J Cancer"},{"key":"ppat.1010045.ref007","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.1056\/NEJM198512193132502","article-title":"Replication of Epstein\u2013Barr Virus within the Epithelial Cells of Oral Hairy Leukoplakia, an AIDS-Associated Lesion","volume":"313","author":"JS Greenspan","year":"1985","journal-title":"N Engl J Med"},{"key":"ppat.1010045.ref008","doi-asserted-by":"crossref","first-page":"16544","DOI":"10.1073\/pnas.1400818111","article-title":"Efficient replication of Epstein\u2013Barr virus in stratified epithelium in vitro","volume":"111","author":"RM Temple","year":"2014","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ppat.1010045.ref009","doi-asserted-by":"crossref","first-page":"e1000496","DOI":"10.1371\/journal.ppat.1000496","article-title":"The Dynamics of EBV Shedding Implicate a Central Role for Epithelial Cells in Amplifying Viral Output.","volume":"5","author":"V 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