{ "abstract": "Kaposi’s sarcoma-associated herpesvirus (KSHV) causes several malignancies in people with HIV including Kaposi’s sarcoma and primary effusion lymphoma (PEL). We have previously shown that PEL cell lines require myeloid cell leukemia-1 (MCL1) to inhibit apoptosis. MCL1 is an oncogene that is amplified in cancers and causes resistance to chemotherapy regimens. MCL1 is thus an attractive target for drug development. The emerging clinical relevance and therapeutic potential of MCL1 motivated us to study the roles of this oncogene in PEL in depth. Using a systems biology approach, we uncovered an unexpected genetic interaction between MCL1 and MARCHF5 indicating that they function in the same pathway. MARCHF5 is an E3 ubiquitin ligase best known for regulating mitochondrial homeostasis and antiviral signaling, but not apoptosis. We thus investigated how MCL1 and MARCHF5 cooperate to promote PEL cell survival. CRISPR knockout (KO) of MARCHF5 in PEL cell lines resulted in a significant increase in apoptosis despite the presence of MCL1. The anti-apoptotic function of MARCHF5 was dependent on its E3 ligase and dimerization activities. Loss of MARCHF5 or inhibition of the 26S proteasome furthermore stabilized the MCL1 antagonist NOXA without affecting levels of MCL1. Interestingly, NOXA KO provides a fitness advantage to PEL cells suggesting that NOXA is the pro-apoptotic signal that necessitates the anti-apoptotic activities of MCL1 and MARCHF5. Endogenous reciprocal co-immunoprecipitation experiments show that MARCHF5 and NOXA are found in the same protein complex. Finally, NOXA KO rescued the loss of cell viability due to MARCHF5 KO. Our findings thus provide the mechanistic link that underlies the genetic interaction between MCL1 and MARCHF5. We propose that MARCHF5 induces the degradation of the MCL1 antagonist NOXA thus reinforcing the pro-survival role of MCL1 in these tumor cells. This newly appreciated interaction of the MCL1 and MARCHF5 oncogenes may be useful to improve the design of combination therapies for KSHV malignancies. Author summary: Kaposi’s sarcoma-associated herpesvirus (KSHV) is a tumor virus that causes the cancers Kaposi’s sarcoma and primary effusion lymphoma (PEL). We previously identified that PEL tumor cells require the oncogene MCL1 to protect cells from apoptosis. In this study, we uncovered that this function is reinforced by another oncogene, MARCHF5. We found that MARCHF5 is similarly required to protect from apoptosis by causing the turnover of the MCL1 antagonist NOXA. By alleviating the inhibitory effect of NOXA on MCL1, we propose that the oncogenes MCL1 and MARCHF5 cooperate in the same pathway to promote tumor cell survival. Understanding this functional reinforcement may be useful in the future to improve the design of combination therapies for KSHV cancers.", "abstract_shown": true, "affiliations": [ "Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America", "Center for Microbial Pathogenesis and Host Inflammatory Responses, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America", "Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America", "Program in Biomedical Engineering, University of Arkansas, Fayetteville, Arkansas, United States of America", "Program in Health Sciences and Interdisciplinary Studies, Hendrix College, Conway, Arkansas, United States of America" ], "article_type": "Research Article", "arxiv": null, "author_total": 10, "authors": [ { "affs": [ 0 ], "name": "Prasanth Viswanathan" }, { "affs": [ 1 ], "name": "Justine R. Bersonda" }, { "affs": [ 2 ], "name": "Jackson Gill" }, { "affs": [ 3 ], "name": "Alyssandra Navarro" }, { "affs": [ 4 ], "name": "Allison C. Farrar" }, { "name": "Thomas Caldarera" }, { "name": "Andrew Murphy" }, { "name": "Daniel Dunham" }, { "name": "Karl W. Boehme" }, { "name": "Mark Manzano" } ], "bibtex": "https://research.draconitic.com/paper/f9td7ycz1wyfe.bib", "cited_by": 0, "doi": "10.1371/journal.ppat.1014665", "fulltext_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014665", "id": "f9td7ycz1wyfe", "issns": [ "1553-7374" ], "landing_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014665", "language": null, "licence": "CC-BY-4.0", "licence_label": "CC BY 4.0", "licence_source": "journal", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "1312|Cell death mechanisms and regulation" ], [ "plos", "/Biology and life sciences/Biochemistry/Bioenergetics/Energy-producing organelles/Mitochondria" ], [ "plos", "/Biology and life sciences/Biochemistry/Enzymology/Enzymes/Ligases/Ubiquitin ligases" ], [ "plos", "/Biology and life sciences/Biochemistry/Nucleic acids/RNA/Guide RNA" ], [ "plos", "/Biology and life sciences/Biochemistry/Proteins/Enzymes/Ligases/Ubiquitin ligases" ], [ "plos", "/Biology and life sciences/Bioengineering/Genome engineering/Synthetic genome editing/CRISPR" ], [ "plos", "/Biology and life sciences/Cell biology/Cell processes/Cell death/Apoptosis" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular structures and organelles/Energy-producing organelles/Mitochondria" ], [ "plos", "/Biology and life sciences/Genetics/Cancer genetics/Oncogenes" ], [ "plos", "/Biology and life sciences/Microbiology/Medical microbiology/Microbial pathogens/Viral pathogens/Retroviruses/Lentivirus" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/RNA viruses/Retroviruses/Lentivirus" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/Viral pathogens/Retroviruses/Lentivirus" ], [ "plos", "/Biology and life sciences/Synthetic biology/Synthetic genomics/Synthetic genome editing/CRISPR" ], [ "plos", "/Engineering and technology/Bioengineering/Genome engineering/Synthetic genome editing/CRISPR" ], [ "plos", "/Engineering and technology/Synthetic biology/Synthetic genomics/Synthetic genome editing/CRISPR" ], [ "plos", "/Medicine and health sciences/Oncology/Cancer treatment" ], [ "plos", "/Medicine and health sciences/Pathology and laboratory medicine/Pathogens/Microbial pathogens/Viral pathogens/Retroviruses/Lentivirus" ] ], "openalex": "W7215089156", "pdf_url": "https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1014665&type=printable", "pmcid": null, "pmid": null, "published": "2026-10-01", "publisher": "Public Library of Science", "ris": "https://research.draconitic.com/paper/f9td7ycz1wyfe.ris", "sources": [ { "first_seen": "2026-10-30T12:17:37Z", "native_id": "10.1371/journal.ppat.1014665", "source": "plos", "url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014665" } ], "subjects": [ { "field": "biology", "origin": "plos:cell biology", "subfield": "cell-biology" }, { "field": "biology", "origin": "plos:bioengineering", "subfield": "systems-synthetic" } ], "title": "The mitochondrial ubiquitin ligase MARCHF5 cooperates with MCL1 to inhibit apoptosis in KSHV-transformed primary effusion lymphoma cell lines", "title_text": "The mitochondrial ubiquitin ligase MARCHF5 cooperates with MCL1 to inhibit apoptosis in KSHV-transformed primary effusion lymphoma cell lines", "type": "peer-reviewed", "updated_at": "2026-10-30T12:17:37Z", "url": "https://research.draconitic.com/paper/f9td7ycz1wyfe", "venue": "PLOS Pathogens", "versions": [] }