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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的这是我们定义EBV介导的代谢控制至关重要的分子基础的最终目标肿瘤发生。在此提案中，我们将重点介绍EBV如何促进氧化的平衡上调磷酸化（OXPHOS）和支持B细胞永生和肿瘤发生的糖酵解。这是我们的中心病毒潜在转录因子EBNA-LP的假设是Oxphos转录的模仿共激活器PGC-1，而糖酵解和氧化还原平衡是通过乳酸的病毒上调维持的转运蛋白MCT1和4。我们根据初步数据提出了中心假设定义EBNA-LP与Oxphos转录因子之间相互作用的正交方法，定义A EBNA-LP上的新的翻译后修饰，并表征了抑制的代谢后果病毒介导的导出。我们发现，病毒EBNA-LP蛋白与NRF-1，ERR和YY-相关联 1模仿细胞共激活器PGC-1。我们描述了EBNA-LP的新型翻译后修饰，羟基化，我们提出的对高阶复合物形成至关重要激活。与EBNA-LP促进的OXPHOS的增加，糖酵解酶的上调通过EBNA2和C-MYC导致乳酸酯在细胞中的积累，必须导出以维持B细胞增殖。我们发现细胞单羧酸盐转运蛋白MCT1和MCT4受到临时调节通过EBV，通过保持NAD+/NADH比和谷胱甘肽水平来维持B细胞增殖活性氧的积累。因此，这项拟议研究的理由是了解B细胞永生化期间EBV如何调节细胞代谢可以揭示新颖的靶向EBV感染的B细胞淋巴瘤的治疗方法。我们计划检验我们的中心假设和通过以下两个特定目的完成本提案中的目标：i）确定分子 EBNA-LP协调EBV调节的氧化物磷酸化以使幼稚B的机制细胞和ii）定义病毒介导的机制，以临时调节单羧酸盐转运蛋白的临时调节， MCT1和4，通过B细胞的产物及其对抗的后果。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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.)
影响因子：
0
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