Host pathways regulating Epstein-Barr virus-mediated B cell growth transformation

调节 Epstein-Barr 病毒介导的 B 细胞生长转化的宿主途径

• 批准号: 10663313
• 负责人: Micah A. Luftig
• 金额: $ 45.63万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10663313
• 关键词: Address; Adult; B Cell Proliferation; B lymphocyte immortalization; B-Cell Lymphomas; B-Lymphocytes; Biochemical; Biogenesis; Cell Proliferation; Cells; Cellular Metabolic Process; Collagen; Complex; Data; Disease; Enzymes; Epithelial Cells; Epstein-Barr Virus Infections; Epstein-Barr Virus latency; Equilibrium; Family; Genetic; Glutathione; Glycolysis; Glycolysis Induction; Goals; Herpesviridae; Human; Human Herpesvirus 4; Human Herpesvirus 8; Immune; Immune response; In Vitro; Infection; LMP1; Lactate Transporter; Leucine; Lymphoma; Lymphomagenesis; Lytic; Lytic Phase; Mediating; Metabolic; Metabolic Control; Metabolism; Mitochondria; Modality; Modeling; Molecular; NADH; Outcome; Oxidation-Reduction; Oxidative Phosphorylation; Pathway interactions; Post-Translational Protein Processing; Proliferating; Proline; Proteins; Reactive Oxygen Species; Regulation; Research; Role; Saliva; Supporting Cell; T-Lymphocyte; Testing; Therapeutic; Transcription Coactivator; Transcriptional Activation; Untranslated RNA; Up-Regulation; Viral; Virus; Virus Latency; Work; antagonist; c-myc Genes; cell growth; cell growth regulation; cell transformation; functional mimics; gammaherpesvirus; in vivo; infected B cell; innovation; latent infection; lymphoblastoid cell line; mimicry; mouse model; neurotensin mimic 1; novel; novel therapeutics; nrf1 protein; oral cavity epithelium; pre-clinical; transcription factor; transmission process; tumorigenesis; virtual

ABSTRACT It is our ultimate goal to define the molecular basis for EBV-mediated metabolic control critical for B-cell tumorigenesis. In this proposal, we will focus on how EBV promotes the balanced upregulation of oxidative phosphorylation (OXPHOS) and glycolysis supporting B-cell immortalization and tumorigenesis. It is our central hypothesis that the viral latent transcription factor, EBNA-LP, functions as a mimic of the OXPHOS transcriptional co-activator PGC-1 while glycolysis and redox balance are maintained through viral upregulation of the lactate transporters MCT1 and 4. We have formulated our central hypothesis based on preliminary data including orthogonal approaches that define interactions between EBNA-LP and OXPHOS transcription factors, define a new post-translational modification on EBNA-LP, and characterize the metabolic consequences of suppressing viral-mediated lactate export. We found that the viral EBNA-LP protein associates with NRF-1, ERR, and YY- 1 mimicking the cellular co-activator PGC-1. We describe a novel post-translational modification of EBNA-LP, hydroxyprolination, that we propose is critical for higher order complex formation enabling transcriptional activation. Balanced with an increase in OXPHOS promoted by EBNA-LP, the upregulation of glycolytic enzymes by EBNA2 and c-MYC leads to an accumulation of lactate in cells that must be exported to sustain B-cell proliferation. We found that cellular monocarboxylate transporters, MCT1 and MCT4, are temporally regulated by EBV to sustain B-cell proliferation through maintaining NAD+/NADH ratios and glutathione levels to counter the accumulation of reactive oxygen species. Therefore, the rationale for this proposed research is that understanding how EBV regulates cellular metabolism during B-cell immortalization could reveal novel therapeutic modalities to target EBV-infected B-cell lymphomas. We plan to test our central hypothesis and complete the objectives in this proposal through the following two specific aims: i) to determine the molecular mechanism by which EBNA-LP coordinates EBV-regulated oxidative phosphorylation to immortalize naïve B cells and ii) to define the viral-mediated mechanism for temporal regulation of the monocarboxylate transporters, MCT1 and 4, through B-cell outgrowth and the consequences of their antagonism.

摘要

项目成果

Use of viral systems to study miRNA-mediated regulation of gene expression in human cells.

使用病毒系统研究人类细胞中 miRNA 介导的基因表达调控。

• DOI: 10.1007/978-1-62703-083-0_12
• 发表时间: 2013
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Forte,Eleonora;Luftig,MicahA
• 通讯作者: Luftig,MicahA

The role of microRNAs in Epstein-Barr virus latency and lytic reactivation.

• DOI: 10.1016/j.micinf.2011.07.007
• 发表时间: 2011-12
• 期刊: Microbes and infection
• 影响因子: 5.8
• 作者: Forte E;Luftig MA
• 通讯作者: Luftig MA

Massively parallel quantification of phenotypic heterogeneity in single-cell drug responses.

• DOI: 10.1126/sciadv.abf9840
• 发表时间: 2021-09-17
• 期刊: Science advances
• 影响因子: 13.6
• 作者: Yellen BB;Zawistowski JS;Czech EA;Sanford CI;SoRelle ED;Luftig MA;Forbes ZG;Wood KC;Hammerbacher J
• 通讯作者: Hammerbacher J