{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T18:28:15Z","timestamp":1790188095463,"version":"4.1.0"},"reference-count":38,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2022,11,23]],"date-time":"2022-11-23T00:00:00Z","timestamp":1669161600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["CA096500, DE028211, CA019014"],"award-info":[{"award-number":["CA096500, DE028211, CA019014"]}]},{"name":"NIH","award":["CA163217, CA254564, CA228172"],"award-info":[{"award-number":["CA163217, CA254564, CA228172"]}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Kaposi\u2019s sarcoma-associated herpesvirus (KSHV) and Epstein-Barr (EBV) are gammaherpesviruses associated with multiple human malignancies. KSHV is the etiological agent of Kaposi\u2019s Sarcoma, primary effusion lymphoma (PEL) and multicentric Castleman\u2019s disease (MCD). EBV is associated with Burkitt\u2019s lymphoma (BL), Hodgkin\u2019s lymphoma (HL), nasopharyngeal carcinoma (NPC) and gastric carcinoma (GC). KSHV and EBV establish life-long latency in the human host with intermittent periods of lytic reactivation. Here, we identified a cellular factor named transforming growth factor-beta regulator 4 (TBRG4) that plays a role in the gammaherpesvirus lifecycle. We find that TBRG4, a protein that is localized to the mitochondria, can regulate lytic reactivation from latency of both KSHV and EBV. Knockdown of TBRG4 in cells latently infected with KSHV or EBV induced viral lytic gene transcription and replication. TBRG4 deficiency causes mitochondrial stress and increases reactive oxygen species (ROS) production. Treatment with a ROS scavenger decreased viral reactivation from latency in TBRG4-depleted cells. These data suggest that TBRG4 serves as a cellular repressor of KSHV and EBV reactivation through the regulation of ROS production.<\/jats:p>","DOI":"10.1371\/journal.ppat.1010990","type":"journal-article","created":{"date-parts":[[2022,11,23]],"date-time":"2022-11-23T22:57:42Z","timestamp":1669244262000},"page":"e1010990","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":18,"title":["Mitochondrial protein, TBRG4, modulates KSHV and EBV reactivation from latency"],"prefix":"10.1371","volume":"18","author":[{"given":"Huirong","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason 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Aids-Related Body-Cavity-Based Lymphomas","volume":"332","author":"E Cesarman","year":"1995","journal-title":"New Engl J Med"},{"issue":"5192","key":"ppat.1010990.ref002","doi-asserted-by":"crossref","first-page":"1865","DOI":"10.1126\/science.7997879","article-title":"Identification of Herpesvirus-Like DNA-Sequences in Aids-Associated Kaposis-Sarcoma","volume":"266","author":"Y Chang","year":"1994","journal-title":"Science"},{"issue":"4","key":"ppat.1010990.ref003","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1182\/blood.V86.4.1276.bloodjournal8641276","article-title":"Kaposis Sarcoma-Associated Herpesvirus-Like DNA-Sequences in Multicentric Castlemans Disease","volume":"86","author":"J Soulier","year":"1995","journal-title":"Blood"},{"issue":"7335","key":"ppat.1010990.ref004","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 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Miller","year":"1997","journal-title":"J Virol"},{"key":"ppat.1010990.ref008","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.semcancer.2014.01.002","article-title":"Regulation of the latent-lytic switch in Epstein-Barr virus","volume":"26","author":"SC Kenney","year":"2014","journal-title":"Semin Cancer Biol"},{"issue":"9","key":"ppat.1010990.ref009","doi-asserted-by":"crossref","DOI":"10.3390\/v12091034","article-title":"Regulation of KSHV Latency and Lytic Reactivation.","volume":"12","author":"G Broussard","year":"2020","journal-title":"Viruses-Basel."},{"issue":"6","key":"ppat.1010990.ref010","doi-asserted-by":"crossref","first-page":"167214","DOI":"10.1016\/j.jmb.2021.167214","article-title":"Activation and Evasion of Innate Immunity by Gammaherpesviruses","volume":"434","author":"PT Lange","year":"2022","journal-title":"J Mol 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Mallery","year":"2004","journal-title":"Carcinogenesis"},{"issue":"3","key":"ppat.1010990.ref014","doi-asserted-by":"crossref","first-page":"1733","DOI":"10.1128\/JVI.02958-12","article-title":"Reactive Oxygen Species Are Induced by Kaposi\u2019s Sarcoma-Associated Herpesvirus Early during Primary Infection of Endothelial Cells To Promote Virus Entry","volume":"87","author":"V Bottero","year":"2013","journal-title":"J Virol"},{"issue":"2","key":"ppat.1010990.ref015","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1128\/JVI.01742-10","article-title":"Oxidative Stress Induces Reactivation of Kaposi\u2019s Sarcoma-Associated Herpesvirus and Death of Primary Effusion Lymphoma Cells","volume":"85","author":"XD Li","year":"2011","journal-title":"J Virol"},{"issue":"5","key":"ppat.1010990.ref016","article-title":"Reactive Oxygen Species Hydrogen Peroxide Mediates Kaposi\u2019s Sarcoma-Associated Herpesvirus Reactivation from Latency.","volume":"7","author":"FC 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lytic reactivation and sensitizes tumors to radiation therapy.","volume":"10","author":"J Hu","year":"2020","journal-title":"Theranostics."},{"issue":"5","key":"ppat.1010990.ref034","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/s41580-018-0092-0","article-title":"Mitochondrial proteins: from biogenesis to functional networks","volume":"20","author":"N Pfanner","year":"2019","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"45","key":"ppat.1010990.ref035","doi-asserted-by":"crossref","first-page":"28384","DOI":"10.1073\/pnas.2011645117","article-title":"A CRISPR-Cas9 screen identifies mitochondrial translation as an essential process in latent KSHV infection of human endothelial cells","volume":"117","author":"DL Holmes","year":"2020","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"7818","key":"ppat.1010990.ref036","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1038\/s41586-020-2077-3","article-title":"A large-scale binding and functional map of human RNA-binding proteins","volume":"583","author":"EL Van Nostrand","year":"2020","journal-title":"Nature"},{"issue":"1","key":"ppat.1010990.ref037","article-title":"The Role of Gammaherpesviruses in Cancer Pathogenesis.","volume":"5","author":"HC Jha","year":"2016","journal-title":"Pathogens"},{"key":"ppat.1010990.ref038","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1089\/crispr.2018.0014","article-title":"EditR: A Method to Quantify Base Editing from Sanger Sequencing.","volume":"1","author":"MG Kluesner","year":"2018","journal-title":"CRISPR J."}],"container-title":["PLOS 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