Germinal center cytokines driven epigenetic control of Epstein-Barr virus latency gene expression

PLoS Pathogens, Journal Year: 2024, Volume and Issue: 20(4), P. e1011939 - e1011939

Published: April 29, 2024

Epstein-Barr virus (EBV) persistently infects 95% of adults worldwide and is associated with multiple human lymphomas that express characteristic EBV latency programs used by the to navigate B-cell compartment. Upon primary infection, III program, comprised six Nuclear Antigens (EBNA) two Latent Membrane Protein (LMP) antigens, drives infected B-cells into germinal center (GC). By incompletely understood mechanisms, GC microenvironmental cues trigger genome switch II EBNA1, LMP1 LMP2A observed in GC-derived Hodgkin lymphoma. To gain insights pathways epigenetic mechanisms control reprogramming as EBV-infected encounter cues, we characterized cytokine effects on protein expression epigenome. We confirmed extended prior studies highlighting support transition. The T-follicular helper interleukin 21 (IL-21), which a major regulator responses, lesser extent IL-4 IL-10, hyper-induced expression, while repressing EBNA expression. However, follicular dendritic cell cytokines including IL-15 IL-27 downmodulate but not CRISPR editing highlighted STAT3 STAT5 were necessary for mediated silencing via at genomic C promoter. contrast, was instead promoter remodeling, activating histone chromatin marks loss repressive polycomb complex marks. Thus, has evolved coopt STAT signaling oppositely regulate status key viral promoters response cues.

Language: Английский

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Insights into the Absence of Lymphoma Despite Fulminant Epstein-Barr Virus Infection in Patients with XIAP Deficiency

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 18, 2025

Abstract X-linked Lymphoproliferative Syndromes (XLP), which arise from mutations in the SH2D1A or XIAP genes, are characterized by inability to control Epstein-Barr Virus (EBV) infection. While primary EBV infection triggers severe diseases each, lymphomas occur at high rates with XLP-1 but not XLP-2. Why XLP-2 patients apparently protected EBV-driven lymphomagenesis, contrast all other described congenital conditions that result heightened susceptibility EBV, remains a key open question. To gain insights, we cross-compared newly infected versus immune stimulated B-cells upon CRISPR knockout, relative healthy controls. perturbation impeded outgrowth of EBV-infected human B-cells, though had no impact on proliferation CD40 ligand and interleukin-21 established EBV-immortalized lymphoblastoid cell lines (LCLs). was depleted editing exhibited markedly lower transformation efficiency than B-cells. Mechanistically, nascent activated p53-mediated apoptosis signaling, whose effects transforming B-cell death were counteracted XIAP. In absence XIAP, triggered apoptosis, seen CD40L/IL-21 stimulation. Moreover, inflammatory cytokines present levels patient serum fulminant infection, induction cells. These findings highlight crucial role supporting early stages immortalization provide insights into EBV+ lymphoma patients. Key points loss-of-function impairs over first week post-infection, particularly presence IFN-γ. mutation impedes potentiating p53-driven caspase activation apoptosis.

Language: Английский

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Epstein-Barr virus latent membrane protein 1 subverts IMPDH pathways to drive B-cell oncometabolism

PLoS Pathogens, Journal Year: 2025, Volume and Issue: 21(5), P. e1013092 - e1013092

Published: May 14, 2025

Epstein-Barr virus (EBV) is associated with multiple types of cancers, many which express the viral oncoprotein Latent Membrane Protein 1 (LMP1). LMP1 contributes to both epithelial and B-cell transformation. Although metabolism reprogramming a cancer hallmark, much remains be learned about how alters lymphocyte oncometabolism. To gain insights into key metabolic pathways subverted by LMP1, we performed systematic metabolomic analyses on B cells conditional expression. This approach highlighted that LMP highly induces de novo purine biosynthesis, xanthosine-5-P (XMP) as one most LMP1-upregulated metabolites. Consequently, IMPDH inhibition mycophenolic acid (MPA) triggered death LMP1-expressing EBV-transformed lymphoblastoid cell lines (LCL), model for EBV-driven immunoblastic lymphomas. Whereas MPA instead caused growth arrest Burkitt lymphoma EBV latency I program, expression their death, this phenotype was rescuable guanosine triphosphate (GTP) supplementation, implicating driver GTP biosynthesis. isozymes are expressed in LCLs, only IMPDH2 critical LCL survival, whereas contributed proliferation program. Both C-terminal cytoplasmic tail domains primary human transformation were important XMP production, each LMP1-driven sensitivity MPA. Metabolomic further roles NF-kB, mitogen activated kinase protein C downstream support abundance. Of these, activity supporting levels expressing cells. also de-repressed lytic antigens, including itself cells, highlighting crosstalk between biosynthesis pathway epigenome. These results suggest novel oncometabolism-based therapeutic approaches

Language: Английский

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Beyond immortality: Epstein-Barr Virus and the intricate dance of programmed cell death in cancer development

Cancer Treatment and Research Communications, Journal Year: 2024, Volume and Issue: 43, P. 100880 - 100880

Published: Jan. 1, 2024

This comprehensive review delves into the intricate role of programmed cell death in Epstein-Barr virus (EBV)-associated malignancies, focusing on sophisticated interplay between viral mechanisms and host's immune response. The central objective is to unravel how EBV exerts control over pathways such as apoptosis, ferroptosis, autophagy, thereby fostering its persistence oncogenic potential. By dissecting these mechanisms, seeks identify therapeutic strategies that could disrupt EBV's manipulation pathways, enhancing recognition opening new avenues for targeted treatment. A deeper understanding molecular underpinnings influence not only enriches field oncology but also pinpoints targets drug development. Furthermore, insights gleaned from this catalyze design vaccines aimed at preventing infection or curtailing impact. Innovatively, synthesizes recent discoveries multifaceted roles non-coding RNAs cellular signaling modulating within context infection. consolidating current knowledge identifying areas where lacking, it lays groundwork future research lead significant advancements vaccine development interventions EBV-related cancers. underscores critical necessity ongoing investigation complex host with ultimate goal patient outcomes EBV-associated diseases.

Language: Английский

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The DNA loop release factor WAPL suppresses Epstein-Barr virus latent membrane protein expression to maintain the highly restricted latency I program

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 10, 2024

Abstract Epstein-Barr virus (EBV) uses latency programs to colonize the memory B-cell reservoir, and each program is associated with human malignancies. However, knowledge remains incomplete of epigenetic mechanisms that maintain highly restricted I program, present in Burkitt lymphoma cells, which EBNA1 only EBV-encoded protein expressed. Given increasing appreciation higher order chromatin architecture an important determinant viral host gene expression, we investigated roles Wings Apart-Like Protein Homolog (WAPL), a factor unloads cohesins control DNA loop size was discovered as EBNA2-associated protein. WAPL knockout (KO) cells de-repressed LMP1 LMP2A expression but not other EBV oncogenes yield reminiscent II, rarely observed B-cells. KO also increased LMP1/2A levels III lymphoblastoid cells. altered genome architecture, triggering formation loops between LMP promoter region origins lytic replication (oriLyt). Hi-C analysis further demonstrated reprograms genomic looping. de-repression correlated decreased histone repressive marks at their promoters. We propose coopts negatively regulate latent membrane I. Author Summary prevalent herpesvirus etiologically linked multiple lymphomas, gastric nasopharyngeal carcinomas, sclerosis. persists B-cells express series programs, distinct type lymphoma. The most form latency, called I, lymphomas. In this state, expressed facilitate infected cell immunoevasion. repress eight proteins remain be fully elucidated. hypothesized might have role restriction genes, it major regulator long-range interactions by regulating cohesin stabilize loops, found yeast 2-hybrid screen for EBNA2-interacting factors. Using CRISPR together Hi-ChIP analyses, uncovered suppressing LMP2A, mimic signaling CD40 immunoglobulin receptors, respectively. These are II program. demonstrate changes including allowing oriLyt enhancers regions. Collectively, our study suggests reinforces preventing may instead support

Language: Английский

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Epstein-Barr Virus Latent Membrane Protein 1 Subverts IMPDH pathways to drive B-cell oncometabolism

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 8, 2024

Abstract Epstein-Barr virus (EBV) is associated with multiple types of cancers, many which express the key viral oncoprotein Latent Membrane Protein 1 (LMP1). LMP1 only EBV-encoded protein whose expression sufficient to transform both epithelial and B-cells. Although metabolism reprogramming a cancer hallmark, much remains be learned about how alters lymphocyte oncometabolism. To gain insights into B-cell metabolic pathways subverted by LMP1, we performed systematic metabolomic analyses on B cells conditional expression. This approach highlighted that LMP highly induces de novo purine biosynthesis, xanthosine-5-P (XMP) as one most LMP1-upregulated metabolites. Consequently, IMPDH inhibition mycophenolic acid (MPA) triggered apoptosis LMP1-expressing EBV-transformed lymphoblastoid cell lines (LCL), model for EBV-driven immunoblastic lymphomas. Whereas MPA instead caused growth arrest Burkitt lymphoma EBV latency I program, their apoptosis. isozymes are expressed in LCLs, IMPDH2 was critical LCL survival, whereas contributed proliferation program. Both C-terminal cytoplasmic tail domains primary human transformation were important XMP production, each LMP1-driven sensitivity MPA. also de-repressed lytic antigens including cells, highlighting crosstalk between biosynthesis pathway epigenome. These results suggest novel oncometabolism-based therapeutic approaches IMPORTANCE Altered hallmark cancer, yet rewires host support malignancies. While oncogene gene murine B-cells rodent fibroblasts, knowledge has remained incomplete oncometabolism aberrantly drive infected survival. Likewise, it unknown whether creates vulnerabilities can targeted small molecule trigger programmed death. We therefore used profiling define signaling remodels metabolome. found upregulated nucleotide likely meet increased demand. sensitized upon inosine monophosphate dehydrogenase blockade. Thus, while itself may not target, its dependence downstream druggable enzymes, suggesting rational approaches.

Language: Английский

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Germinal Center Cytokines Driven Epigenetic Control of Epstein-Barr Virus Latency Gene Expression

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 3, 2024

Abstract Epstein-Barr virus (EBV) persistently infects 95% of adults worldwide and is associated with multiple human lymphomas that express characteristic EBV latency programs used by the to navigate B-cell compartment. Upon primary infection, III program, comprised six Nuclear Antigens (EBNA) two Latent Membrane Protein (LMP) antigens, drives infected B-cells into germinal center (GC). By incompletely understood mechanisms, GC microenvironmental cues trigger genome switch II EBNA1, LMP1 LMP2A observed in GC-derived Hodgkin lymphoma. To gain insights pathways epigenetic mechanisms control reprogramming as EBV-infected encounter cues, we characterized cytokine effects on protein expression epigenome. We confirmed extended prior studies highlighting support transition. The T-follicular helper interleukin 21 (IL-21), which a major regulator responses, lesser extent IL-4 IL-10, hyper-induced expression, while repressing EBNA expression. However, follicular dendritic cell cytokines including IL-15 IL-27 downmodulate but not CRISPR editing highlighted STAT3 STAT5 were necessary for mediated silencing via at genomic C promoter. contrast, was instead promoter remodeling, activating histone chromatin marks loss repressive polycomb complex marks. Thus, has evolved coopt STAT signaling oppositely regulate status key viral promoters response cues. Author Summary A longstanding question remained how epigenetically switches between it navigates uses its program stimulate newly B growth then trafficking secondary lymphoid tissue centers In III, stimulates nuclear antigens turn induce latent membrane proteins (LMP). knowledge incomplete about switching II, where only one LMP are expressed, Building evidence cue, systematically tested secreted GC-resident T cells gene remodeling their promoters. This range repress EBNA, several events transition programs. identified downstream roles JAK/STAT relaying signals epigenome, obligatory 5 rewiring

Language: Английский

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The DNA loop release factor WAPL suppresses Epstein-Barr virus latent membrane protein expression to maintain the highly restricted latency I program

PLoS Pathogens, Journal Year: 2024, Volume and Issue: 20(9), P. e1012525 - e1012525

Published: Sept. 6, 2024

Epstein-Barr virus (EBV) uses latency programs to colonize the memory B-cell reservoir, and each program is associated with human malignancies. However, knowledge remains incomplete of epigenetic mechanisms that maintain highly restricted I program, present in Burkitt lymphoma cells, which EBNA1 only EBV-encoded protein expressed. Given increasing appreciation higher order chromatin architecture an important determinant viral host gene expression, we investigated roles Wings Apart-Like Protein Homolog (WAPL), a factor unloads cohesin control DNA loop size was discovered as EBNA2-associated protein. WAPL knockout (KO) cells de-repressed LMP1 LMP2A but not other EBV oncogenes, yield reminiscent II, rarely observed B-cells. KO also increased LMP1/2A levels III lymphoblastoid cells. altered genome architecture, triggering formation loops between LMP promoter region origins lytic replication ( oriLyt ). Hi-C analysis further demonstrated reprogrammed genomic looping. de-repression correlated decreased histone repressive marks at their promoters. We propose coopts negatively regulate latent membrane expression I.

Language: Английский

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Ubiquitin-Mediated Effects on Oncogenesis during EBV and KSHV Infection

Viruses, Journal Year: 2024, Volume and Issue: 16(10), P. 1523 - 1523

Published: Sept. 26, 2024

The

Language: Английский

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