Effects of Ethanol on Proteasome-HCV Core Protein Interactions

乙醇对蛋白酶体-HCV 核心蛋白相互作用的影响

• 批准号: 7783877
• 负责人: NATALIA ALEKSANDR OSNA
• 金额: $ 15.59万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-10 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7783877
• 关键词: Affect; Alcohol abuse; Alcohol consumption; Alcohols; Antigen Presentation; Cells; Chronic; Chronic Hepatitis C; Clinical; Complex; Core Protein; Cytokine Signaling; Cytotoxic T-Lymphocytes; Disease; Enzymes; Ethanol; Ethanol Metabolism; Event; Future; Generations; Hepatitis C; Hepatitis C virus; Hepatocyte; Hydrolysis; Immune response; Immune system; Infection; Injury; Investigation; Knowledge; Language; Link; Liver; MHC Class I Genes; Oxidative Stress; Patients; Peptides; Population; Process; Proteasome Binding; Proteins; Proteolysis; Regulation; Research; Risk; Signal Transduction; Structural Protein; Testing; Therapeutic; Transgenic Mice; Viral Antigens; Viral Proteins; Viremia; Virulence; adaptive immunity; alcohol effect; alcohol exposure; drinking; feeding; hepatitis C virus nucleocapsid protein; improved; multicatalytic endopeptidase complex; problem drinker; protein degradation; vaccine development; virus core; virus pathogenesis

DESCRIPTION (provided by applicant): In HCV infection, about 70% of patients develop persistent viremia and chronic course of infection. Alcohol abuse strongly accelerates the progression of HCV infection. One of HCV structural proteins, known as core protein, induces oxidative stress in liver cells, and this is further potentiated by ethanol. Oxidative stress modulates the functions of many enzymes, including the multi-catalytic protein-degrading enzyme, the proteasome. This enzyme degrades oxidatively modified proteins, signal transduction factors and processes peptides for antigen presentation. We hypothesize that HCV core protein enhances proteasome activity by directly interacting with the enzyme and indirectly, by inducing low levels of oxidative stress. However, in ethanol-exposed liver cells, proteasome activation by core protein is blocked by ethanol metabolism, which suppresses proteasome activity. Potentially, these changes in proteasome activity may affect protein degradation and generation of peptides for antigen presentation. To test this hypothesis, we propose two Specific Aims. Aim 1 will ascertain the mechanism(s) of proteasome activation by HCV core protein and determine whether ethanol metabolism blocks proteasome activation by core protein. Aim 2 will determine whether HCV core protein affects proteasome activity and overall intracellular proteolysis in HCV core-expressing cells and in core-expressing control and ethanol-fed transgenic mice. The results derived from this study will help clarify the mechanism of alcohol-potentiated HCV progression, providing a link between altered proteasome function and processing of HCV peptides for presentation by infected liver cells. This investigation will also provide the framework for future HCV pathogenetic studies, namely, proteasome-dependent regulation of cytokine signaling and MHC class I-resticted presentation of HCV antigens to cytotoxic T-lymphocytes. Both transduction of cytokine signals and antigen presentation can be suppressed by ethanol metabolism. Lay Language Summary: The proposed study will expand our knowledge in the mechanisms of how hepatitis C viral protein and ethanol regulate the enzyme, which degrades proteins. The results of this investigation will partially explain why the immune system is less able to clear HCV in alcoholic compared to in non-drinking patients. We envision that this research will potentially have therapeutic applications, helping to improve chronic hepatitis C treatment and vaccine development

描述(申请人提供)：在丙型肝炎病毒感染中，约70%的患者出现持续性病毒血症和慢性感染过程。酗酒强烈地加速了丙型肝炎病毒感染的进展。丙型肝炎病毒结构蛋白之一，被称为核心蛋白，在肝细胞中诱导氧化应激，而乙醇进一步加强了这一作用。氧化应激调节许多酶的功能，包括多催化蛋白质降解酶，即蛋白酶体。这种酶降解氧化修饰的蛋白质、信号转导因子，并处理多肽以供抗原呈递。我们假设，丙型肝炎病毒核心蛋白通过直接与酶相互作用和通过诱导低水平的氧化应激来间接增强蛋白酶体的活性。然而，在乙醇暴露的肝细胞中，核心蛋白对蛋白酶体的激活被乙醇代谢所阻断，从而抑制了蛋白酶体的活性。潜在地，这些蛋白酶体活性的变化可能会影响蛋白质的降解和抗原呈递多肽的产生。为了检验这一假设，我们提出了两个具体目标。目的1探讨丙型肝炎病毒核心蛋白激活蛋白酶体的机制(S)，以及乙醇代谢是否阻断核心蛋白激活蛋白酶体。目的2确定丙型肝炎病毒核心蛋白是否影响核心表达细胞、核心表达对照和乙醇喂养转基因小鼠的蛋白酶体活性和整体细胞内蛋白分解。这项研究的结果将有助于阐明酒精增强的丙型肝炎病毒进展的机制，提供蛋白酶体功能改变与处理丙型肝炎病毒多肽以供受感染的肝细胞呈递之间的联系。这项研究也将为未来的丙型肝炎病原学研究提供框架，即蛋白酶体依赖的细胞因子信号的调节和MHC-I类抗原向细胞毒性T淋巴细胞的递呈。细胞因子信号转导和抗原递呈均可被乙醇代谢抑制。外行语言摘要：这项拟议的研究将扩大我们对丙型肝炎病毒蛋白和乙醇如何调节降解蛋白质的酶的机制的了解。这项研究的结果将部分解释为什么与不饮酒的患者相比，免疫系统清除酗酒患者的丙型肝炎病毒的能力较差。我们预计，这项研究将具有潜在的治疗应用，有助于改进慢性丙型肝炎的治疗和疫苗开发

项目成果

Impaired methylation as a novel mechanism for proteasome suppression in liver cells.

甲基化受损是肝细胞中蛋白酶体抑制的新机制。

• DOI: 10.1016/j.bbrc.2009.12.074
• 发表时间: 2010
• 期刊: Biochemical and biophysical research communications
• 影响因子: 3.1
• 作者: Osna,NataliaA;White,RondaL;DonohueJr,TerrenceM;Beard,MichaelR;Tuma,DeanJ;Kharbanda,KusumK
• 通讯作者: Kharbanda,KusumK