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: 8582219
• 负责人: Young Bong Choi
• 金额: $ 22.84万
• 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 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8582219
• 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）：人类疱疹病毒 8 (HHV-8) 编码非结构蛋白，通过多重抑制相互作用调节宿主细胞抗病毒机制。我们发现病毒干扰素调节因子-1 (vIRF-1) 通过核隔离 (Bim) 抑制 BH3 蛋白 (BOP) 的促凋亡活性，包括 Bim 和 Bid，或直接抑制它们诱导线粒体释放细胞色素 c。此外，我们发现 vIRF-1 可以独立于其与 BOP 的相互作用而定位于线粒体，并特异性靶向线粒体耐去污剂膜组分 (mitoDRM)（一种脂筏）。 MitoDRM 最近被确定为线粒体功能上重要的微结构域，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 mitoDRM 的重要性日益增加，但人们对 mitoDRM 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 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至关重要。此外，vIRF-1 与线粒体共定位于类似于线粒体自噬过程中发生的聚集体中，表明 vIRF-1 在线粒体质量控制和相关细胞存活中可能发挥作用。为了确定 vIRF-1 通过 mitoDRM 靶向和细胞保护对 HHV-8 复制的贡献，该提案重点检查：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，该提案将研究病毒与宿主相互作用的新范例，并可能为基于已确定的相互作用和机制的新型抗病毒药物的未来开发提供基础。