{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T15:28:30Z","timestamp":1792337310489,"version":"4.4.0"},"reference-count":124,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2024,9,26]],"date-time":"2024-09-26T00:00:00Z","timestamp":1727308800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIAID","award":["1R21AI180281-01A1"],"award-info":[{"award-number":["1R21AI180281-01A1"]}]},{"name":"NYMC","award":["1R21AI180281-01A1"],"award-info":[{"award-number":["1R21AI180281-01A1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>The Herpesviridae include the Epstein\u2013Barr Virus (EBV) and the Kaposi Sarcoma-associated Herpesvirus (KSHV), both of which are oncogenic gamma-herpesviruses. These viruses manipulate host cellular mechanisms, including through ubiquitin-mediated pathways, to promote viral replication and oncogenesis. Ubiquitin, a regulatory protein which tags substrates for degradation or alters their function, is manipulated by both EBV and KSHV to facilitate viral persistence and cancer development. EBV infects approximately 90% of the global population and is implicated in malignancies including Burkitt lymphoma (BL), Hodgkin lymphoma (HL), post-transplant lymphoproliferative disorder (PTLD), and nasopharyngeal carcinoma. EBV latency proteins, notably LMP1 and EBNA3C, use ubiquitin-mediated mechanisms to inhibit apoptosis, promote cell proliferation, and interfere with DNA repair, contributing to tumorigenesis. EBV\u2019s lytic proteins, including BZLF1 and BPLF1, further disrupt cellular processes to favor oncogenesis. Similarly, KSHV, a causative agent of Kaposi\u2019s Sarcoma and lymphoproliferative disorders, has a latency-associated nuclear antigen (LANA) and other latency proteins that manipulate ubiquitin pathways to degrade tumor suppressors, stabilize oncogenic proteins, and evade immune responses. KSHV\u2019s lytic cycle proteins, such as RTA and Orf64, also use ubiquitin-mediated strategies to impair immune functions and promote oncogenesis. This review explores the ubiquitin-mediated interactions of EBV and KSHV proteins, elucidating their roles in viral oncogenesis. Understanding these mechanisms offers insights into the similarities between the viruses, as well as provoking thought about potential therapeutic targets for herpesvirus-associated cancers.<\/jats:p>","DOI":"10.3390\/v16101523","type":"journal-article","created":{"date-parts":[[2024,9,26]],"date-time":"2024-09-26T09:46:20Z","timestamp":1727343980000},"page":"1523","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Ubiquitin-Mediated Effects on Oncogenesis during EBV and KSHV Infection"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-9027-9822","authenticated-orcid":false,"given":"Rachel","family":"Mund","sequence":"first","affiliation":[{"name":"Department of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, NY 10595, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4740-2317","authenticated-orcid":false,"given":"Christopher B.","family":"Whitehurst","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, NY 10595, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,26]]},"reference":[{"key":"ref_1","unstructured":"Baron, S. (1996). Herpesviruses. Medical Microbiology, University of Texas Medical Branch. [4th ed.]."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1128\/jvi.63.2.943-947.1989","article-title":"During latency, herpes simplex virus type 1 DNA is associated with nucleosomes in a chromatin structure","volume":"63","author":"Deshmane","year":"1989","journal-title":"J. Virol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1016\/j.tim.2012.08.005","article-title":"A cultured affair: HSV latency and reactivation in neurons","volume":"20","author":"Wilson","year":"2012","journal-title":"Trends Microbiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3652","DOI":"10.1016\/j.cell.2022.08.026","article-title":"Epstein-Barr Virus: Biology and Clinical Disease","volume":"185","author":"Damania","year":"2022","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.coviro.2021.11.004","article-title":"The Regulation of Kshv Lytic Reactivation by Viral and Cellular Factors","volume":"52","author":"Sandhu","year":"2022","journal-title":"Curr. Opin. Virol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1016\/S0140-6736(64)91524-7","article-title":"Virus Particles in Cultured Lymphoblasts from Burkitt\u2019s Lymphoma","volume":"1","author":"Epstein","year":"1964","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1056\/NEJM198902233200806","article-title":"Detection of Epstein-Barr viral genomes in Reed-Sternberg cells of Hodgkin\u2019s disease","volume":"320","author":"Weiss","year":"1989","journal-title":"N. Engl. J. Med."},{"key":"ref_8","first-page":"297","article-title":"Epstein-Barr virus and nasopharyngeal carcinoma","volume":"3","year":"1992","journal-title":"Semin. Cancer Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1038\/2281056a0","article-title":"EBV DNA in biopsies of Burkitt tumours and anaplastic carcinomas of the nasopharynx","volume":"228","author":"Klein","year":"1970","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1016\/0140-6736(91)91837-K","article-title":"Epstein-Barr virus in AIDS-related primary central nervous system lymphoma","volume":"338","author":"MacMahon","year":"1991","journal-title":"Lancet"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.1212\/WNL.0000000000004412","article-title":"Epstein-Barr virus, cytomegalovirus, and multiple sclerosis susceptibility: A multiethnic study","volume":"89","author":"Wu","year":"2017","journal-title":"Neurology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.msard.2017.05.009","article-title":"Epstein-Barr virus and multiple sclerosis: Updating Pender\u2019s hypothesis","volume":"16","author":"Laurence","year":"2017","journal-title":"Mult. Scler. Relat. Disord."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"310","DOI":"10.7326\/0003-4819-75-2-310","article-title":"Cancer in the immunosuppressed patient","volume":"75","author":"Fahey","year":"1971","journal-title":"Ann. Intern. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1865","DOI":"10.1126\/science.7997879","article-title":"Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi\u2019s sarcoma","volume":"266","author":"Chang","year":"1994","journal-title":"Science"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.1056\/NEJM199505043321802","article-title":"Kaposi\u2019s sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas","volume":"332","author":"Cesarman","year":"1995","journal-title":"N. Engl. J. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1182\/blood.V86.4.1276.bloodjournal8641276","article-title":"Kaposi\u2019s sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman\u2019s disease","volume":"86","author":"Soulier","year":"1995","journal-title":"Blood"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1086\/654798","article-title":"An interleukin-6-related systemic inflammatory syndrome in patients co-infected with Kaposi sarcoma-associated herpesvirus and HIV but without Multicentric Castleman disease","volume":"51","author":"Uldrick","year":"2010","journal-title":"Clin. Infect. Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1006\/scdb.2000.0164","article-title":"Ubiquitination and deubiquitination: Targeting of proteins for degradation by the proteasome","volume":"11","author":"Wilkinson","year":"2000","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Lee, J.Y., An, E.K., Hwang, J., Jin, J.O., and Lee, P.C.W. (2021). Ubiquitin Activating Enzyme UBA6 Regulates Th1 and Tc1 Cell Differentiation. Cells, 11.","DOI":"10.3390\/cells11010105"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1096\/fj.09-136259","article-title":"The family of ubiquitin-conjugating enzymes (E2s): Deciding between life and death of proteins","volume":"24","author":"Timmers","year":"2010","journal-title":"FASEB J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1038\/cr.2016.39","article-title":"Ubiquitin modifications","volume":"26","author":"Swatek","year":"2016","journal-title":"Cell Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1006\/viro.2002.1562","article-title":"Lysine-independent ubiquitination of Epstein-Barr virus LMP2A","volume":"300","author":"Ikeda","year":"2002","journal-title":"Virology"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"McClellan, A.J., Laugesen, S.H., and Ellgaard, L. (2019). Cellular functions and molecular mechanisms of non-lysine ubiquitination. Open Biol., 9.","DOI":"10.1098\/rsob.190147"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1038\/s41580-022-00543-1","article-title":"An expanded lexicon for the ubiquitin code","volume":"24","author":"Dikic","year":"2023","journal-title":"Nat. Rev. Mol. Cell. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1146\/annurev.biochem.78.082307.091526","article-title":"Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes","volume":"78","author":"Ventii","year":"2009","journal-title":"Annu. Rev. Biochem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"6323","DOI":"10.1128\/JVI.76.12.6323-6331.2002","article-title":"Deubiquitinating function of adenovirus proteinase","volume":"76","author":"Balakirev","year":"2002","journal-title":"J. Virol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1016\/j.molcel.2005.07.003","article-title":"A deubiquitinating enzyme encoded by HSV-1 belongs to a family of cysteine proteases that is conserved across the family Herpesviridae","volume":"19","author":"Kattenhorn","year":"2005","journal-title":"Mol. Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4345","DOI":"10.1128\/JVI.02195-08","article-title":"The Epstein-Barr virus (EBV) deubiquitinating enzyme BPLF1 reduces EBV ribonucleotide reductase activity","volume":"83","author":"Whitehurst","year":"2009","journal-title":"J. Virol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4619","DOI":"10.1128\/JVI.02406-09","article-title":"Deubiquitinating and interferon antagonism activities of coronavirus papain-like proteases","volume":"84","author":"Clementz","year":"2010","journal-title":"J. Virol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1016\/j.chom.2007.09.014","article-title":"Ovarian tumor domain-containing viral proteases evade ubiquitin- and ISG15-dependent innate immune responses","volume":"2","author":"Giannakopoulos","year":"2007","journal-title":"Cell Host Microbe"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3758","DOI":"10.1128\/JVI.02589-10","article-title":"The leader proteinase of foot-and-mouth disease virus negatively regulates the type I interferon pathway by acting as a viral deubiquitinase","volume":"85","author":"Wang","year":"2011","journal-title":"J. Virol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.semcdb.2021.10.011","article-title":"Herpesvirus ubiquitin deconjugases","volume":"132","author":"Masucci","year":"2022","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.coviro.2013.04.005","article-title":"The pathogenesis of Epstein-Barr virus persistent infection","volume":"3","author":"Hawkins","year":"2013","journal-title":"Curr. Opin. Virol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Price, A.M., and Luftig, M.A. (2015). To be or not IIb: A multi-step process for Epstein-Barr virus latency establishment and consequences for B cell tumorigenesis. PLoS Pathog., 11.","DOI":"10.1371\/journal.ppat.1004656"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Oeckinghaus, A., and Ghosh, S. (2009). The NF-kappaB family of transcription factors and its regulation. Cold Spring Harb. Perspect. Biol., 1.","DOI":"10.1101\/cshperspect.a000034"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1016\/j.febslet.2008.01.031","article-title":"The activation of p53 mediated by Epstein-Barr virus latent membrane protein 1 in SV40 large T-antigen transformed cells","volume":"582","author":"Li","year":"2008","journal-title":"FEBS Lett."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"8801","DOI":"10.2147\/CMAR.S260583","article-title":"The Anti-Apoptotic Role of EBV-LMP1 in Lymphoma Cells","volume":"12","author":"Zeng","year":"2020","journal-title":"Cancer Manag. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2491","DOI":"10.1128\/JVI.01681-08","article-title":"MDM2-dependent inhibition of p53 is required for Epstein-Barr virus B-cell growth transformation and infected-cell survival","volume":"83","author":"Forte","year":"2009","journal-title":"J. Virol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1101\/gad.7.7a.1126","article-title":"The p53-mdm-2 autoregulatory feedback loop","volume":"7","author":"Wu","year":"1993","journal-title":"Genes Dev."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.virusres.2007.05.013","article-title":"Ubiquitination of MDM2 modulated by Epstein-Barr virus encoded latent membrane protein 1","volume":"130","author":"Li","year":"2007","journal-title":"Virus Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"4535","DOI":"10.1182\/blood-2003-03-0870","article-title":"Proteasomal targeting of a viral oncogene abrogates oncogenic phenotype and enhances immunogenicity","volume":"102","author":"Tellam","year":"2003","journal-title":"Blood"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1038\/s41467-020-14502-x","article-title":"A central role of IKK2 and TPL2 in JNK activation and viral B-cell transformation","volume":"11","author":"Voigt","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Mitra, B., Beri, N.R., Guo, R., Burton, E.M., Murray-Nerger, L.A., and Gewurz, B.E. (2023). Characterization of target gene regulation by the two Epstein-Barr virus oncogene LMP1 domains essential for B-cell transformation. mBio, 14.","DOI":"10.1128\/mbio.02338-23"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Greenfeld, H., Takasaki, K., Walsh, M.J., Ersing, I., Bernhardt, K., Ma, Y., Fu, B., Ashbaugh, C.W., Cabo, J., and Mollo, S.B. (2015). TRAF1 Coordinates Polyubiquitin Signaling to Enhance Epstein-Barr Virus LMP1-Mediated Growth and Survival Pathway Activation. PLoS Pathog., 11.","DOI":"10.1371\/journal.ppat.1004890"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.virol.2013.10.018","article-title":"KSHV LANA and EBV LMP1 induce the expression of UCH-L1 following viral transformation","volume":"448","author":"Bentz","year":"2014","journal-title":"Virology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1038\/s41419-017-0081-9","article-title":"Epstein-Barr virus encoded latent membrane protein 1 suppresses necroptosis through targeting RIPK1\/3 ubiquitination","volume":"9","author":"Liu","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"18431","DOI":"10.1073\/pnas.0504054102","article-title":"Up-regulation of beta-catenin by a viral oncogene correlates with inhibition of the seven in absentia homolog 1 in B lymphoma cells","volume":"102","author":"Jang","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"9870","DOI":"10.1158\/0008-5472.CAN-06-1679","article-title":"EBV latent membrane protein 1 up-regulates hypoxia-inducible factor 1alpha through Siah1-mediated down-regulation of prolyl hydroxylases 1 and 3 in nasopharyngeal epithelial cells","volume":"66","author":"Kondo","year":"2006","journal-title":"Cancer Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1186\/s13046-023-02835-6","article-title":"Anoikis resistance and immune escape mediated by Epstein-Barr virus-encoded latent membrane protein 1-induced stabilization of PGC-1alpha promotes invasion and metastasis of nasopharyngeal carcinoma","volume":"42","author":"Liao","year":"2023","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.bbrc.2017.07.105","article-title":"RPS27a enhances EBV-encoded LMP1-mediated proliferation and invasion by stabilizing of LMP1","volume":"491","author":"Hong","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_51","first-page":"e1138-16","article-title":"The Linear Ubiquitin Assembly Complex Modulates Latent Membrane Protein 1 Activation of NF-kappaB and Interferon Regulatory Factor 7","volume":"91","author":"Wang","year":"2017","journal-title":"J. Virol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"8526","DOI":"10.1128\/MCB.20.22.8526-8535.2000","article-title":"Latent membrane protein 2A of Epstein-Barr virus binds WW domain E3 protein-ubiquitin ligases that ubiquitinate B-cell tyrosine kinases","volume":"20","author":"Winberg","year":"2000","journal-title":"Mol. Cell. Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1006\/viro.1999.0166","article-title":"The Epstein-Barr virus latent membrane protein 2A PY motif recruits WW domain-containing ubiquitin-protein ligases","volume":"268","author":"Ikeda","year":"2000","journal-title":"Virology"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"5711","DOI":"10.1128\/JVI.75.12.5711-5718.2001","article-title":"PY motifs of Epstein-Barr virus LMP2A regulate protein stability and phosphorylation of LMP2A-associated proteins","volume":"75","author":"Ikeda","year":"2001","journal-title":"J. Virol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"13803","DOI":"10.1128\/JVI.02203-13","article-title":"Epstein-Barr virus latent membrane protein 2 effects on epithelial acinus development reveal distinct requirements for the PY and YEEA motifs","volume":"87","author":"Fotheringham","year":"2013","journal-title":"J. Virol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2516","DOI":"10.1182\/blood-2017-07-796821","article-title":"EBV latent membrane protein 2A orchestrates p27(kip1) degradation via Cks1 to accelerate MYC-driven lymphoma in mice","volume":"130","author":"Fish","year":"2017","journal-title":"Blood"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1042\/BST0320731","article-title":"HAUSP\/USP7 as an Epstein-Barr virus target","volume":"32","author":"Holowaty","year":"2004","journal-title":"Biochem. Soc. Trans."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"11113","DOI":"10.1128\/JVI.01183-10","article-title":"Epstein-Barr virus nuclear antigen 1 Hijacks the host kinase CK2 to disrupt PML nuclear bodies","volume":"84","author":"Sivachandran","year":"2010","journal-title":"J. Virol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2014","DOI":"10.1128\/jvi.67.4.2014-2025.1993","article-title":"Epstein-Barr virus nuclear proteins EBNA-3A and EBNA-3C are essential for B-lymphocyte growth transformation","volume":"67","author":"Tomkinson","year":"1993","journal-title":"J. Virol."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Saha, A., Halder, S., Upadhyay, S.K., Lu, J., Kumar, P., Murakami, M., Cai, Q., and Robertson, E.S. (2011). Epstein-Barr virus nuclear antigen 3C facilitates G1-S transition by stabilizing and enhancing the function of cyclin D1. PLoS Pathog., 7.","DOI":"10.1371\/journal.ppat.1001275"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1128\/JVI.00663-18","article-title":"Epstein-Barr Virus Nuclear Antigen 3C Facilitates Cell Proliferation by Regulating Cyclin D2","volume":"92","author":"Pei","year":"2018","journal-title":"J. Virol."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Zhang, S., Pei, Y., Lang, F., Sun, K., Singh, R.K., Lamplugh, Z.L., Saha, A., and Robertson, E.S. (2019). EBNA3C facilitates RASSF1A downregulation through ubiquitin-mediated degradation and promoter hypermethylation to drive B-cell proliferation. PLoS Pathog., 15.","DOI":"10.1371\/journal.ppat.1007514"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Pei, Y., Banerjee, S., Jha, H.C., Sun, Z., and Robertson, E.S. (2017). An essential EBV latent antigen 3C binds Bcl6 for targeted degradation and cell proliferation. PLoS Pathog., 13.","DOI":"10.1371\/journal.ppat.1006500"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Banerjee, S., Lu, J., Cai, Q., Sun, Z., Jha, H.C., and Robertson, E.S. (2014). EBNA3C augments Pim-1 mediated phosphorylation and degradation of p21 to promote B-cell proliferation. PLoS Pathog., 10.","DOI":"10.1371\/journal.ppat.1004304"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"3776","DOI":"10.1128\/JVI.03568-13","article-title":"Epstein-Barr virus essential antigen EBNA3C attenuates H2AX expression","volume":"88","author":"Jha","year":"2014","journal-title":"J. Virol."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Ohashi, M., Holthaus, A.M., Calderwood, M.A., Lai, C.Y., Krastins, B., Sarracino, D., and Johannsen, E. (2015). The EBNA3 family of Epstein-Barr virus nuclear proteins associates with the USP46\/USP12 deubiquitination complexes to regulate lymphoblastoid cell line growth. PLoS Pathog., 11.","DOI":"10.1371\/journal.ppat.1004822"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1128\/MCB.25.5.1749-1763.2005","article-title":"SCFSkp2 complex targeted by Epstein-Barr virus essential nuclear antigen","volume":"25","author":"Knight","year":"2005","journal-title":"Mol. Cell. Biol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"7453","DOI":"10.1128\/JVI.79.12.7453-7465.2005","article-title":"Induction of Kaposi\u2019s sarcoma-associated herpesvirus latency-associated nuclear antigen by the lytic transactivator RTA: A novel mechanism for establishment of latency","volume":"79","author":"Lan","year":"2005","journal-title":"J. Virol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/B978-0-12-385032-4.00003-3","article-title":"Molecular biology of Kaposi\u2019s sarcoma-associated herpesvirus and related oncogenesis","volume":"78","author":"Cai","year":"2010","journal-title":"Adv. Virus Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1038\/nrc2888","article-title":"Kaposi\u2019s sarcoma and its associated herpesvirus","volume":"10","author":"Mesri","year":"2010","journal-title":"Nat. Rev. Cancer"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.canlet.2009.07.004","article-title":"Kaposi sarcoma-associated herpesvirus (KSHV): Molecular biology and oncogenesis","volume":"289","author":"Wen","year":"2010","journal-title":"Cancer Lett."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1128\/MCB.01011-13","article-title":"p53 tumor suppressor protein stability and transcriptional activity are targeted by Kaposi\u2019s sarcoma-associated herpesvirus-encoded viral interferon regulatory factor 3","volume":"34","author":"Baresova","year":"2014","journal-title":"Mol. Cell. Biol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1038\/47266","article-title":"p53 inhibition by the LANA protein of KSHV protects against cell death","volume":"402","author":"Friborg","year":"1999","journal-title":"Nature"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1038\/80459","article-title":"The latent nuclear antigen of Kaposi sarcoma-associated herpesvirus targets the retinoblastoma-E2F pathway and with the oncogene Hras transforms primary rat cells","volume":"6","author":"Radkov","year":"2000","journal-title":"Nat. Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1172\/JCI26190","article-title":"The latency-associated nuclear antigen of Kaposi sarcoma-associated herpesvirus induces B cell hyperplasia and lymphoma","volume":"116","author":"Fakhari","year":"2006","journal-title":"J. Clin. Investig."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"7367","DOI":"10.1128\/JVI.00554-14","article-title":"Kaposi\u2019s sarcoma-associated herpesvirus-encoded LANA can induce chromosomal instability through targeted degradation of the mitotic checkpoint kinase Bub1","volume":"88","author":"Sun","year":"2014","journal-title":"J. Virol."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Cai, Q.L., Knight, J.S., Verma, S.C., Zald, P., and Robertson, E.S. (2006). EC5S ubiquitin complex is recruited by KSHV latent antigen LANA for degradation of the VHL and p53 tumor suppressors. PLoS Pathog., 2.","DOI":"10.1371\/journal.ppat.0020116"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Cai, Q., Xiao, B., Si, H., Cervini, A., Gao, J., Lu, J., Upadhyay, S.K., Verma, S.C., and Robertson, E.S. (2012). Kaposi\u2019s sarcoma herpesvirus upregulates Aurora A expression to promote p53 phosphorylation and ubiquitylation. PLoS Pathog., 8.","DOI":"10.1371\/journal.ppat.1002566"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1038\/nm829","article-title":"A novel viral mechanism for dysregulation of beta-catenin in Kaposi\u2019s sarcoma-associated herpesvirus latency","volume":"9","author":"Fujimuro","year":"2003","journal-title":"Nat. Med."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"10451","DOI":"10.1128\/JVI.00804-07","article-title":"The Kaposi\u2019s sarcoma-associated herpesvirus LANA protein stabilizes and activates c-Myc","volume":"81","author":"Liu","year":"2007","journal-title":"J. Virol."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Kim, Y.J., Kim, Y., Kumar, A., Kim, C.W., Toth, Z., Cho, N.H., and Lee, H.R. (2021). Kaposi\u2019s sarcoma-associated herpesvirus latency-associated nuclear antigen dysregulates expression of MCL-1 by targeting FBW7. PLoS Pathog., 17.","DOI":"10.1371\/journal.ppat.1009179"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"16287","DOI":"10.1073\/pnas.0703508104","article-title":"Kaposi\u2019s sarcoma herpesvirus-encoded latency-associated nuclear antigen stabilizes intracellular activated Notch by targeting the Sel10 protein","volume":"104","author":"Lan","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2268","DOI":"10.1128\/JVI.02742-14","article-title":"Kaposi\u2019s sarcoma-associated herpesvirus induces Nrf2 activation in latently infected endothelial cells through SQSTM1 phosphorylation and interaction with polyubiquitinated Keap1","volume":"89","author":"Gjyshi","year":"2015","journal-title":"J. Virol."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Valiya Veettil, M., Dutta, D., Bottero, V., Bandyopadhyay, C., Gjyshi, O., Sharma-Walia, N., Dutta, S., and Chandran, B. (2014). Glutamate secretion and metabotropic glutamate receptor 1 expression during Kaposi\u2019s sarcoma-associated herpesvirus infection promotes cell proliferation. PLoS Pathog., 10.","DOI":"10.1371\/journal.ppat.1004389"},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Rosemarie, Q., and Sugden, B. (2020). Epstein-Barr Virus: How Its Lytic Phase Contributes to Oncogenesis. Microorganisms, 8.","DOI":"10.3390\/microorganisms8111824"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.virol.2009.03.017","article-title":"Expression of Epstein-Barr virus BZLF1 immediate-early protein induces p53 degradation independent of MDM2, leading to repression of p53-mediated transcription","volume":"388","author":"Sato","year":"2009","journal-title":"Virology"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1128\/JVI.01512-10","article-title":"A new model of Epstein-Barr virus infection reveals an important role for early lytic viral protein expression in the development of lymphomas","volume":"85","author":"Ma","year":"2011","journal-title":"J. Virol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"5340","DOI":"10.1128\/JVI.00250-13","article-title":"Kaposi\u2019s sarcoma-associated herpesvirus-encoded viral IRF3 modulates major histocompatibility complex class II (MHC-II) antigen presentation through MHC-II transactivator-dependent and -independent mechanisms: Implications for oncogenesis","volume":"87","author":"Zuo","year":"2013","journal-title":"J. Virol."},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Lin, L.T., Lu, Y.S., Huang, H.H., Chen, H., Hsu, S.W., and Chang, L.K. (2022). Regulation of Epstein-Barr Virus Minor Capsid Protein BORF1 by TRIM5alpha. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232315340"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"15582","DOI":"10.1128\/JVI.79.24.15582-15585.2005","article-title":"A deubiquitinating activity is conserved in the large tegument protein of the herpesviridae","volume":"79","author":"Schlieker","year":"2005","journal-title":"J. Virol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"8097","DOI":"10.1128\/JVI.00588-12","article-title":"Epstein-Barr virus BPLF1 deubiquitinates PCNA and attenuates polymerase eta recruitment to DNA damage sites","volume":"86","author":"Whitehurst","year":"2012","journal-title":"J. Virol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"e01574-15","DOI":"10.1128\/mBio.01574-15","article-title":"Knockout of Epstein-Barr virus BPLF1 retards B-cell transformation and lymphoma formation in humanized mice","volume":"6","author":"Whitehurst","year":"2015","journal-title":"mBio"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"4060","DOI":"10.1128\/JVI.02020-12","article-title":"Epstein-Barr virus deubiquitinase downregulates TRAF6-mediated NF-kappaB signaling during productive replication","volume":"87","author":"Saito","year":"2013","journal-title":"J. Virol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"e00600-17","DOI":"10.1128\/JVI.00600-17","article-title":"The Translesion Polymerase Pol eta Is Required for Efficient Epstein-Barr Virus Infectivity and Is Regulated by the Viral Deubiquitinating Enzyme BPLF1","volume":"91","author":"Dyson","year":"2017","journal-title":"J. Virol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"6411","DOI":"10.1128\/JVI.00536-14","article-title":"The Rad6\/18 ubiquitin complex interacts with the Epstein-Barr virus deubiquitinating enzyme, BPLF1, and contributes to virus infectivity","volume":"88","author":"Kumar","year":"2014","journal-title":"J. Virol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"101012","DOI":"10.1016\/j.neo.2024.101012","article-title":"Epstein-Barr virus deubiquitinating enzyme BPLF1 is involved in EBV carcinogenesis by affecting cellular genomic stability","volume":"55","author":"Wu","year":"2024","journal-title":"Neoplasia"},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Li, J., Nagy, N., Liu, J., Gupta, S., Frisan, T., Hennig, T., Cameron, D.P., Baranello, L., and Masucci, M.G. (2021). The Epstein-Barr virus deubiquitinating enzyme BPLF1 regulates the activity of topoisomerase II during productive infection. PLoS Pathog., 17.","DOI":"10.1101\/2021.02.26.433008"},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"van Gent, M., Braem, S.G., de Jong, A., Delagic, N., Peeters, J.G., Boer, I.G., Moynagh, P.N., Kremmer, E., Wiertz, E.J., and Ovaa, H. (2014). Epstein-Barr virus large tegument protein BPLF1 contributes to innate immune evasion through interference with toll-like receptor signaling. PLoS Pathog., 10.","DOI":"10.1371\/journal.ppat.1003960"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"3461","DOI":"10.1080\/15548627.2021.1874660","article-title":"The Epstein-Barr virus deubiquitinase BPLF1 targets SQSTM1\/p62 to inhibit selective autophagy","volume":"17","author":"Gupta","year":"2021","journal-title":"Autophagy"},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Lui, W.Y., Bharti, A., Wong, N.M., Jangra, S., Botelho, M.G., Yuen, K.S., and Jin, D.Y. (2023). Suppression of cGAS- and RIG-I-mediated innate immune signaling by Epstein-Barr virus deubiquitinase BPLF1. PLoS Pathog., 19.","DOI":"10.1371\/journal.ppat.1011186"},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Gupta, S., Yla-Anttila, P., Callegari, S., Tsai, M.H., Delecluse, H.J., and Masucci, M.G. (2018). Herpesvirus deconjugases inhibit the IFN response by promoting TRIM25 autoubiquitination and functional inactivation of the RIG-I signalosome. PLoS Pathog., 14.","DOI":"10.1371\/journal.ppat.1006852"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1128\/JVI.02183-15","article-title":"The Missing Link in Epstein-Barr Virus Immune Evasion: The BDLF3 Gene Induces Ubiquitination and Downregulation of Major Histocompatibility Complex Class I (MHC-I) and MHC-II","volume":"90","author":"Quinn","year":"2016","journal-title":"J. Virol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"e00258-20","DOI":"10.1128\/JVI.00258-20","article-title":"Epstein-Barr Virus (EBV) Tegument Protein BGLF2 Suppresses Type I Interferon Signaling To Promote EBV Reactivation","volume":"94","author":"Liu","year":"2020","journal-title":"J. Virol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"e0102721","DOI":"10.1128\/JVI.01027-21","article-title":"Suppression of JAK-STAT Signaling by Epstein-Barr Virus Tegument Protein BGLF2 through Recruitment of SHP1 Phosphatase and Promotion of STAT2 Degradation","volume":"95","author":"Jangra","year":"2021","journal-title":"J. Virol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"800","DOI":"10.1128\/JVI.79.2.800-811.2005","article-title":"Virion proteins of Kaposi\u2019s sarcoma-associated herpesvirus","volume":"79","author":"Zhu","year":"2005","journal-title":"J. Virol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"10224","DOI":"10.1128\/JVI.00589-09","article-title":"Kaposi\u2019s sarcoma-associated herpesvirus encodes a viral deubiquitinase","volume":"83","author":"Gonzalez","year":"2009","journal-title":"J. Virol."},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Aneja, K.K., and Yuan, Y. (2017). Reactivation and Lytic Replication of Kaposi\u2019s Sarcoma-Associated Herpesvirus: An Update. Front. Microbiol., 8.","DOI":"10.3389\/fmicb.2017.00613"},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Pardieu, C., Vigan, R., Wilson, S.J., Calvi, A., Zang, T., Bieniasz, P., Kellam, P., Towers, G.J., and Neil, S.J. (2010). The RING-CH ligase K5 antagonizes restriction of KSHV and HIV-1 particle release by mediating ubiquitin-dependent endosomal degradation of tetherin. PLoS Pathog., 6.","DOI":"10.1371\/journal.ppat.1000843"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"9335","DOI":"10.1128\/JVI.00873-14","article-title":"Kaposi\u2019s sarcoma-associated herpesvirus K3 and K5 ubiquitin E3 ligases have stage-specific immune evasion roles during lytic replication","volume":"88","author":"Brulois","year":"2014","journal-title":"J. Virol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"2233","DOI":"10.1038\/s41418-022-01011-1","article-title":"A viral interferon regulatory factor degrades RNA-binding protein hnRNP Q1 to enhance aerobic glycolysis via recruiting E3 ubiquitin ligase KLHL3 and decaying GDPD1 mRNA","volume":"29","author":"Qi","year":"2022","journal-title":"Cell Death Differ."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1128\/JVI.02591-14","article-title":"Kaposi\u2019s sarcoma-associated herpesvirus-encoded replication and transcription activator impairs innate immunity via ubiquitin-mediated degradation of myeloid differentiation factor 88","volume":"89","author":"Zhao","year":"2015","journal-title":"J. Virol."},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"Gu, F., Wang, C., Wei, F., Wang, Y., Zhu, Q., Ding, L., Xu, W., Zhu, C., Cai, C., and Qian, Z. (2018). STAT6 degradation and ubiquitylated TRIML2 are essential for activation of human oncogenic herpesvirus. PLoS Pathog., 14.","DOI":"10.1371\/journal.ppat.1007416"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"10899","DOI":"10.1128\/JVI.00690-11","article-title":"Inhibition of RIG-I-mediated signaling by Kaposi\u2019s sarcoma-associated herpesvirus-encoded deubiquitinase ORF64","volume":"85","author":"Inn","year":"2011","journal-title":"J. Virol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1038\/onc.2013.595","article-title":"Structural proteins of Kaposi\u2019s sarcoma-associated herpesvirus antagonize p53-mediated apoptosis","volume":"34","author":"Chudasama","year":"2015","journal-title":"Oncogene"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"6281","DOI":"10.1074\/jbc.M115.710632","article-title":"Identification of Kaposi Sarcoma Herpesvirus (KSHV) vIRF1 Protein as a Novel Interaction Partner of Human Deubiquitinase USP7","volume":"291","author":"Chavoshi","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.1038\/nsmb.2142","article-title":"Bilateral inhibition of HAUSP deubiquitinase by a viral interferon regulatory factor protein","volume":"18","author":"Lee","year":"2011","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"1980","DOI":"10.1128\/JVI.01911-10","article-title":"Phosphorylation and polyubiquitination of transforming growth factor beta-activated kinase 1 are necessary for activation of NF-kappaB by the Kaposi\u2019s sarcoma-associated herpesvirus G protein-coupled receptor","volume":"85","author":"Bottero","year":"2011","journal-title":"J. Virol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"2994","DOI":"10.1073\/pnas.1601860113","article-title":"Endolysosomal trafficking of viral G protein-coupled receptor functions in innate immunity and control of viral oncogenesis","volume":"113","author":"Dong","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"37641","DOI":"10.1074\/jbc.M110.132415","article-title":"Identification of a lysosomal pathway regulating degradation of the bone morphogenetic protein receptor type II","volume":"285","author":"Durrington","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"9615","DOI":"10.1128\/JVI.02633-07","article-title":"Remodeling of endothelial adherens junctions by Kaposi\u2019s sarcoma-associated herpesvirus","volume":"82","author":"Mansouri","year":"2008","journal-title":"J. Virol."},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Karki, R., Lang, S.M., and Means, R.E. (2011). The MARCH family E3 ubiquitin ligase K5 alters monocyte metabolism and proliferation through receptor tyrosine kinase modulation. PLoS Pathog., 7.","DOI":"10.1371\/journal.ppat.1001331"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"5186","DOI":"10.4049\/jimmunol.0902938","article-title":"Kaposi\u2019s sarcoma-associated herpesvirus K3 and K5 proteins block distinct steps in transendothelial migration of effector memory CD4+ T cells by targeting different endothelial proteins","volume":"184","author":"Manes","year":"2010","journal-title":"J. Immunol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"2117","DOI":"10.1128\/JVI.01961-06","article-title":"Downregulation of gamma interferon receptor 1 by Kaposi\u2019s sarcoma-associated herpesvirus K3 and K5","volume":"81","author":"Li","year":"2007","journal-title":"J. Virol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"2077","DOI":"10.4049\/jimmunol.165.4.2077","article-title":"Impaired CTL recognition of cells latently infected with Kaposi\u2019s sarcoma-associated herpes virus","volume":"165","author":"Brander","year":"2000","journal-title":"J. Immunol."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/16\/10\/1523\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:04:07Z","timestamp":1760112247000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/16\/10\/1523"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,26]]},"references-count":124,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2024,10]]}},"alternative-id":["v16101523"],"URL":"https:\/\/doi.org\/10.3390\/v16101523","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,26]]}}}