The mitochondrial ubiquitin ligase MARCHF5 cooperates with MCL1 to inhibit apoptosis in KSHV-transformed primary effusion lymphoma cell lines
5 affiliations
- 1Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America
- 2Center for Microbial Pathogenesis and Host Inflammatory Responses, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America
- 3Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America
- 4Program in Biomedical Engineering, University of Arkansas, Fayetteville, Arkansas, United States of America
- 5Program in Health Sciences and Interdisciplinary Studies, Hendrix College, Conway, Arkansas, United States of America
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.
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BibTeX
@article{viswanathan2026mitochondrial,
title = {{The mitochondrial ubiquitin ligase MARCHF5 cooperates with MCL1 to inhibit apoptosis in KSHV-transformed primary effusion lymphoma cell lines}},
author = {Prasanth Viswanathan and Justine R. Bersonda and Jackson Gill and Alyssandra Navarro and Allison C. Farrar and Thomas Caldarera and Andrew Murphy and Daniel Dunham and Karl W. Boehme and Mark Manzano},
journal = {PLOS Pathogens},
year = {2026},
month = oct,
doi = {10.1371/journal.ppat.1014665},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014665},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - The mitochondrial ubiquitin ligase MARCHF5 cooperates with MCL1 to inhibit apoptosis in KSHV-transformed primary effusion lymphoma cell lines
AU - Prasanth Viswanathan
AU - Justine R. Bersonda
AU - Jackson Gill
AU - Alyssandra Navarro
AU - Allison C. Farrar
AU - Thomas Caldarera
AU - Andrew Murphy
AU - Daniel Dunham
AU - Karl W. Boehme
AU - Mark Manzano
PY - 2026
DA - 2026/10/01
JO - PLOS Pathogens
DO - 10.1371/journal.ppat.1014665
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014665
AB - 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.
SN - 1553-7374
ER -