{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T17:51:23Z","timestamp":1778003483787,"version":"3.51.4"},"reference-count":70,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T00:00:00Z","timestamp":1755648000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Health","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>Epstein-Barr Virus (EBV) is a causative agent of infectious mononucleosis and is strongly associated with Burkitt lymphoma, Hodgkin lymphoma, and nasopharyngeal carcinoma. EBV encodes a deubiquitinating enzyme, BPLF1, which is important for infectious virus production, B-cell immortalization, and tumorigenesis. To elucidate BPLF1\u2019s role, an affinity-based mass spectrometry screen was performed, which suggested that BPLF1 and mTOR interact. mTOR, a critical mediator within cellular signaling cascades and oncogenesis, exists in two distinct complexes: mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2). Here, we show that BPLF1 has direct deubiquitinating (DUB) activity on mTOR, removing both K48- and K63-ubiquitin linkages. Additionally, WT BPLF1 decreased mTORC1 localization to the lysosome and decreased the phosphorylation of mTORC1 downstream effectors, 4E-BP1 and S6K1. BPLF1 also had DUB activity on Raptor and Rictor, which have both been shown to preferentially cause the formation of mTORC2 over mTORC1 when not ubiquitinated. Immunoprecipitation of mTOR shows decreased mTORC1 formation in the presence of WT BPLF1. Importantly, treatment with rapamycin, an mTORC1 inhibitor, increased infectious virus production, while JR-AB2-011, an mTORC2 inhibitor, reduced infectious virus production. Taken together, these data demonstrate that BPLF1\u2019s effect on the mTOR signaling cascade regulates cellular and viral processes during EBV infectivity and replication.<\/jats:p>","DOI":"10.3390\/v17081139","type":"journal-article","created":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T07:50:46Z","timestamp":1755676246000},"page":"1139","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Novel Role of the Epstein-Barr Virus Encoded Deubiquitinating Enzyme (BPLF1) in mTOR-Mediated Cell Growth and Proliferation Pathways"],"prefix":"10.3390","volume":"17","author":[{"given":"Rachel","family":"Mund","sequence":"first","affiliation":[{"name":"Department of Pathology, Microbiology and Immunology, New York Medical College, New York, NY 10595, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sage L.","family":"Atkins","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of North Carolina Chapel Hill, Chapel Hill, NC 27599, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anwen","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology and Immunology, New York Medical College, New York, NY 10595, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aminatou","family":"Diallo","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology and Immunology, New York Medical College, New York, NY 10595, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher B.","family":"Whitehurst","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology and Immunology, New York Medical College, New York, NY 10595, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,20]]},"reference":[{"key":"ref_1","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_2","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. 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