{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T06:34:54Z","timestamp":1773297294420,"version":"3.50.1"},"reference-count":40,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2019,12,16]],"date-time":"2019-12-16T00:00:00Z","timestamp":1576454400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"publisher","award":["19K07580, 17H04081"],"award-info":[{"award-number":["19K07580, 17H04081"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP17fm0208016, JP16ek0109098"],"award-info":[{"award-number":["JP17fm0208016, JP16ek0109098"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","award":["na"],"award-info":[{"award-number":["na"]}],"id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005694","name":"Hori Sciences and Arts Foundation","doi-asserted-by":"publisher","award":["na"],"award-info":[{"award-number":["na"]}],"id":[{"id":"10.13039\/501100005694","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>Epstein-Barr virus (EBV) is a member of the gammaherpesvirinae, which causes infectious mononucleosis and several types of cancer. BBRF2 is an uncharacterized gene of EBV and is expressed during the lytic phase. To evaluate its function, BBRF2-knockout EBV was prepared using bacterial artificial chromosome (BAC) technology and the CRISPR\/Cas9 system. Although viral gene expression, DNA synthesis, and progeny secretion were not affected, the infectivity of progeny viruses was significantly reduced by the disruption of BBRF2. When expressed alone, BBRF2 protein localized to the nucleus and cytoplasm, while the coexpression of an interacting partner, BSRF1, resulted in its relocalization to the cytoplasm. Interestingly, the coexpression of BBRF2 protected BSRF1 from proteasome\/ubiquitin-dependent degradation. Therefore, BBRF2, together with BSRF1, augments viral infectivity.<\/jats:p>","DOI":"10.3390\/microorganisms7120705","type":"journal-article","created":{"date-parts":[[2019,12,17]],"date-time":"2019-12-17T02:59:01Z","timestamp":1576551541000},"page":"705","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Epstein-Barr Virus BBRF2 Is Required for Maximum Infectivity"],"prefix":"10.3390","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0953-2471","authenticated-orcid":false,"given":"H. M. Abdullah Al","family":"Masud","sequence":"first","affiliation":[{"name":"Department of Virology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan"},{"name":"Department of Microbiology, Faculty of Biological Sciences, University of Chittagong, Chattogram 4331, Bangladesh"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yusuke","family":"Yanagi","sequence":"additional","affiliation":[{"name":"Department of Virology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7249-8106","authenticated-orcid":false,"given":"Takahiro","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Department of Virology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8541-6413","authenticated-orcid":false,"given":"Yoshitaka","family":"Sato","sequence":"additional","affiliation":[{"name":"Department of Virology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroshi","family":"Kimura","sequence":"additional","affiliation":[{"name":"Department of Virology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takayuki","family":"Murata","sequence":"additional","affiliation":[{"name":"Department of Virology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan"},{"name":"Department of Virology and Parasitology, Fujita Health University School of Medicine, Toyoakev 470-1192, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,12,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1038\/nrc1452","article-title":"Epstein-Barr virus: 40 Years on","volume":"4","author":"Young","year":"2004","journal-title":"Nat. Rev. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2068","DOI":"10.1002\/pbc.24654","article-title":"Epstein-Barr virus (EBV) positive classical Hodgkin lymphoma of Iraqi children: An immunophenotypic and molecular characterization of Hodgkin\/Reed-Sternberg cells","volume":"60","author":"Talerico","year":"2013","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_3","first-page":"71","article-title":"Chromatin structure of Epstein-Barr virus latent episomes","volume":"390","author":"Lieberman","year":"2015","journal-title":"Curr. Top Microbiol. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1111\/1348-0421.12155","article-title":"Regulation of Epstein-Barr virus reactivation from latency","volume":"58","author":"Murata","year":"2014","journal-title":"Microbiol. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1007\/978-981-10-7230-7_18","article-title":"Encyclopedia of EBV-encoded lytic genes: An update","volume":"1045","author":"Murata","year":"2018","journal-title":"Adv. Exp Med. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"16286","DOI":"10.1073\/pnas.0407320101","article-title":"Proteins of purified Epstein-Barr virus","volume":"101","author":"Johannsen","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e02196-16","DOI":"10.1128\/JVI.02196-16","article-title":"Dual function of the pUL7-pUL51 tegument protein complex in herpes simplex virus 1 infection","volume":"91","author":"Albecka","year":"2017","journal-title":"J. Virol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3112","DOI":"10.1128\/JVI.02799-14","article-title":"The herpes simplex virus 1 UL51 protein interacts with the UL7 protein and plays a role in its recruitment into the virion","volume":"89","author":"Roller","year":"2015","journal-title":"J. Virol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"11291","DOI":"10.1128\/JVI.79.17.11291-11299.2005","article-title":"The UL7 gene of pseudorabies virus encodes a nonessential structural protein which is involved in virion formation and egress","volume":"79","author":"Fuchs","year":"2005","journal-title":"J. Virol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4058","DOI":"10.1128\/JVI.03707-13","article-title":"The herpes simplex virus 1 UL51 gene product has cell type-specific functions in cell-to-cell spread","volume":"88","author":"Roller","year":"2014","journal-title":"J. Virol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1128\/jvi.70.2.1091-1099.1996","article-title":"Identification and characterization of the bovine herpesvirus 1 UL7 gene and gene product which are not essential for virus replication in cell culture","volume":"70","author":"Schmitt","year":"1996","journal-title":"J. Virol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5125","DOI":"10.1128\/JVI.01682-10","article-title":"Cytomegalovirus UL103 controls virion and dense body egress","volume":"85","author":"Ahlqvist","year":"2011","journal-title":"J. Virol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"9086","DOI":"10.1128\/JVI.01141-14","article-title":"Identification of human cytomegalovirus genes important for biogenesis of the cytoplasmic virion assembly complex","volume":"88","author":"Das","year":"2014","journal-title":"J. Virol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Butnaru, M., and Gaglia, M.M. (2019). The Kaposi\u2019s sarcoma-associated herpesvirus protein ORF42 is required for efficient virion production and expression of viral proteins. Viruses, 11.","DOI":"10.3390\/v11080711"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3805","DOI":"10.1073\/pnas.0404521102","article-title":"Identification of viral genes essential for replication of murine gamma-herpesvirus 68 using signature-tagged mutagenesis","volume":"102","author":"Song","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Yanagi, Y., Masud, H., Watanabe, T., Sato, Y., Goshima, F., Kimura, H., and Murata, T. (2019). Initial characterization of the Epstein(-)Barr virus BSRF1 gene product. Viruses, 11.","DOI":"10.3390\/v11030285"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3204","DOI":"10.1128\/JVI.77.5.3204-3216.2003","article-title":"Subcellular localization of herpes simplex virus type 1 UL51 protein and role of palmitoylation in Golgi apparatus targeting","volume":"77","author":"Nozawa","year":"2003","journal-title":"J. Virol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e01035-18","DOI":"10.1128\/JVI.01035-18","article-title":"Roles of the phosphorylation of herpes simplex virus 1 UL51 at a specific site in viral replication and pathogenicity","volume":"92","author":"Kato","year":"2018","journal-title":"J. Virol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3831","DOI":"10.1128\/JVI.79.6.3831-3840.2005","article-title":"Functional analysis of the pseudorabies virus UL51 protein","volume":"79","author":"Klupp","year":"2005","journal-title":"J. Virol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2331","DOI":"10.1099\/vir.0.012831-0","article-title":"Quantitative evaluation of the role of Epstein-Barr virus immediate-early protein BZLF1 in B-cell transformation","volume":"90","author":"Katsumura","year":"2009","journal-title":"J. Gen. Virol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5125","DOI":"10.1128\/JVI.02674-05","article-title":"Epstein-Barr virus protein kinase BGLF4 is a virion tegument protein that dissociates from virions in a phosphorylation-dependent process and phosphorylates the viral immediate-early protein BZLF1","volume":"80","author":"Asai","year":"2006","journal-title":"J. Virol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3409","DOI":"10.1128\/JVI.79.6.3409-3418.2005","article-title":"Architecture of replication compartments formed during Epstein-Barr virus lytic replication","volume":"79","author":"Daikoku","year":"2005","journal-title":"J. Virol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.virol.2019.02.015","article-title":"The BOLF1 gene is necessary for effective Epstein-Barr viral infectivity","volume":"531","author":"Masud","year":"2019","journal-title":"Virology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e00975-17","DOI":"10.1128\/JVI.00975-17","article-title":"Epstein-Barr virus BKRF4 gene product is required for efficient progeny production","volume":"91","author":"Masud","year":"2017","journal-title":"J. Virol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.virol.2009.04.007","article-title":"Efficient production of infectious viruses requires enzymatic activity of Epstein-Barr virus protein kinase","volume":"389","author":"Murata","year":"2009","journal-title":"Virology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e00138-e18","DOI":"10.1128\/mSphere.00138-18","article-title":"BGLF2 increases infectivity of Epstein-Barr virus by activating AP-1 upon de novo infection","volume":"3","author":"Konishi","year":"2018","journal-title":"mSphere"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"8245","DOI":"10.1073\/pnas.95.14.8245","article-title":"Propagation and recovery of intact, infectious Epstein-Barr virus from prokaryotic to human cells","volume":"95","author":"Delecluse","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2120","DOI":"10.1128\/JVI.02634-12","article-title":"Pin1 interacts with the Epstein-Barr virus DNA polymerase catalytic subunit and regulates viral DNA replication","volume":"87","author":"Narita","year":"2013","journal-title":"J. Virol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"20788","DOI":"10.1074\/jbc.M600563200","article-title":"Ubiquitination and proteasome-dependent degradation of human eukaryotic translation initiation factor 4E","volume":"281","author":"Murata","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Fossum, E., Friedel, C.C., Rajagopala, S.V., Titz, B., Baiker, A., Schmidt, T., Kraus, T., Stellberger, T., Rutenberg, C., and Suthram, S. (2009). Evolutionarily conserved herpesviral protein interaction networks. PLoS Pathog., 5.","DOI":"10.1371\/journal.ppat.1000570"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1128\/JVI.02555-13","article-title":"Elucidation of the block to herpes simplex virus egress in the absence of tegument protein UL16 reveals a novel interaction with VP22","volume":"88","author":"Starkey","year":"2014","journal-title":"J. Virol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"9647","DOI":"10.1128\/JVI.01126-12","article-title":"Characterization and intracellular trafficking of Epstein-Barr virus BBLF1, a protein involved in virion maturation","volume":"86","author":"Chiu","year":"2012","journal-title":"J. Virol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5339","DOI":"10.1128\/JVI.77.9.5339-5351.2003","article-title":"The pseudorabies virus UL11 protein is a virion component involved in secondary envelopment in the cytoplasm","volume":"77","author":"Kopp","year":"2003","journal-title":"J. Virol."},{"key":"ref_34","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_35","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_36","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.virol.2014.02.003","article-title":"The interaction of the HSV-1 tegument proteins pUL36 and pUL37 is essential for secondary envelopment during viral egress","volume":"454","author":"Kelly","year":"2014","journal-title":"Virology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1111\/cmi.12075","article-title":"Cytosolic herpes simplex virus capsids not only require binding inner tegument protein pUL36 but also pUL37 for active transport prior to secondary envelopment","volume":"15","author":"Sandbaumhuter","year":"2013","journal-title":"Cell Microbiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"125","DOI":"10.3389\/fmicb.2017.00125","article-title":"The C-terminus of Epstein-Barr virus BRRF2 is required for its proper localization and efficient virus production","volume":"8","author":"Watanabe","year":"2017","journal-title":"Front. Microbiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.virol.2015.05.010","article-title":"The Epstein-Barr virus BRRF2 gene product is involved in viral progeny production","volume":"484","author":"Watanabe","year":"2015","journal-title":"Virology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.virol.2015.04.007","article-title":"Roles of Epstein-Barr virus BGLF3.5 gene and two upstream open reading frames in lytic viral replication in HEK293 cells","volume":"483","author":"Watanabe","year":"2015","journal-title":"Virology"}],"container-title":["Microorganisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2607\/7\/12\/705\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:42:47Z","timestamp":1760190167000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2607\/7\/12\/705"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,16]]},"references-count":40,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["microorganisms7120705"],"URL":"https:\/\/doi.org\/10.3390\/microorganisms7120705","relation":{},"ISSN":["2076-2607"],"issn-type":[{"value":"2076-2607","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,16]]}}}