Mitochondrial DRM targeting by HHV-8 viral interferon regulatory factor-1

HHV-8 病毒干扰素调节因子 1 靶向线粒体 DRM

• 批准号: 8660616
• 负责人: Young Bong Choi
• 金额: $ 20.25万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-15 至 2015-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8660616
• 关键词: Antiviral Agents; Apoptosis; Apoptotic; Attenuated; Binding; Biological; Biological Assay; Biological Process; Biology; Carbonyl Cyanide m-Chlorophenyl Hydrazone; Cell Death; Cell Survival; Cells; Co-Immunoprecipitations; Coupled; Cytoprotection; Data; Degenerative Disorder; Detergents; Development; Disease; Drug Targeting; Endopeptidase K; Future; Human Herpesvirus 8; Immune response; In Vitro; Interferon Regulatory Factor 1; Length; Lipid Binding; Malignant Neoplasms; Membrane; Membrane Microdomains; Mitochondria; Molecular; Molecular Chaperones; Molecular Target; Mutagenesis; N-terminal; Nuclear; Pathogenesis; Peptides; Play; Precipitation; Proline-Rich Domain; Protein Binding Domain; Proteins; Quality Control; Refractory; Research; Resistance; Role; Stress; Techniques; Testing; Variant; Viral Proteins; Virus; Virus Diseases; Yeasts; base; cytochrome c; design; novel; overexpression; pro-apoptotic protein; public health relevance; receptor; treatment strategy; viral interferon regulatory factor; viral interferon regulatory factor-1; virus host interaction; yeast two hybrid system

DESCRIPTION (provided by applicant): Human herpesvirus 8 (HHV-8) encodes non-structural proteins that regulate host cell antiviral mechanisms via multiple inhibitory interactions. We have found that viral interferon regulatory factor-1 (vIRF-1) inhibits the pro-apoptotic activity of BH3-only proteins (BOPs) including Bim and Bid by nuclear sequestration (Bim) or directly suppressing their induction of cytochrome c release from mitochondria. In addition, we have found that vIRF-1 can localize to mitochondria independently of its interaction with BOPs and specifically targets mitochondrial detergent-resistant membrane fractions (mitoDRMs), a type of lipid raft. MitoDRMs have been recently identified as a functionally important microdomain of mitochondria and emerged as an attractive target for the treatment of a variety of degenerative diseases and cancer. Despite the increasing significance of mitoDRMs, little is known about the role of mitoDRMs in virus infection. To our knowledge, vIRF-1 is the first viral protein known to target to mitoDRMs. Furthermore, our preliminary data have shown that the N-terminal proline-rich domain (PD, 1-75 residues) of vIRF-1 is essential for mitoDRM targeting and protects cells from mitochondrial damage. Also, vIRF-1 co-localizes with mitochondria in an aggregate resembling those occurring during mitophagy, indicating a possible role of vIRF-1 in mitochondria quality control and associated cell survival. To determine the contribution of vIRF-1 through mitoDRM targeting and cell protection to HHV-8 replication, this proposal focuses on examining: 1) the novel structural determinants of mitoDRM targeting by vIRF-1 PD; 2) the molecular mechanisms of vIRF-1 mitoDRM anchoring and cell protection; 3) the functional significance of mitoDRM-localized vIRF-1 in mitophagy and HHV-8 replication. This proposal will thus examine a novel paradigm of virus-host interaction, and potentially provide a basis for future development of novel antiviral agents based on the identified interactions and mechanisms.

描述（由申请人提供）：人疱疹病毒8型（HHV-8）编码通过多种抑制性相互作用调节宿主细胞抗病毒机制的非结构蛋白。我们已经发现，病毒干扰素调节因子-1（vIRF-1）通过核螯合（Bim）或直接抑制其诱导细胞色素c从线粒体释放来抑制BH 3-only蛋白（BOP）（包括Bim和Bid）的促凋亡活性。此外，我们发现vIRF-1可以定位于线粒体，而不依赖于其与BOP的相互作用，并特异性靶向线粒体耐洗涤剂膜组分（mitoDRMs），一种脂筏。MitoDRM最近被鉴定为线粒体的功能重要的微结构域，并成为治疗各种退行性疾病和癌症的有吸引力的靶标。尽管mitoDRMs的重要性日益增加，但对mitoDRMs在病毒感染中的作用知之甚少。据我们所知，vIRF-1是已知的第一个靶向mitoDRM的病毒蛋白。此外，我们的初步数据表明，vIRF-1的N-末端富含脯氨酸的结构域（PD，1-75个残基）对于mitoDRM靶向和保护细胞免受线粒体损伤是必需的。此外，vIRF-1与线粒体共定位在类似于线粒体自噬期间发生的聚集体中，表明vIRF-1在线粒体质量控制和相关细胞存活中的可能作用。为了确定vIRF-1通过mitoDRM靶向和细胞保护对HHV-8复制的贡献，该提议重点检查：1）vIRF-1 PD靶向mitoDRM的新结构决定因素; 2）vIRF-1 mitoDRM锚定和细胞保护的分子机制; 3）mitoDRM定位的vIRF-1在线粒体自噬和HHV-8复制中的功能意义。因此，这一建议将检查一个新的病毒-宿主相互作用的范例，并可能提供一个基础上确定的相互作用和机制的基础上，未来开发新的抗病毒药物。