权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mechanism and Function of Mitophagy Regulation by HHV-8 Viral Interferon Regulatory Factor-1

HHV-8病毒干扰素调节因子1调控线粒体自噬的机制和功能

基本信息

批准号：
10158457
负责人：
Young Bong Choi
金额：
$ 37.46万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10158457
关键词：
AIDS related cancer Acquired Immunodeficiency Syndrome Affect Antiviral Agents Antiviral Response Apoptosis Autophagocytosis Binding Biological Biology CASP5 gene Caspase Cells Characteristics Chemicals Common Neoplasm Data Development Disease Enzymes Etiology Excision Family Future Goals HIV Human Herpesvirus 8 Impairment Individual Infection Interferons Kaposi Sarcoma Knock-out Lead Link Lymphoma cell Lytic Maps Mediating Mitochondria Molecular Multicentric Angiofollicular Lymphoid Hyperplasia Mutate Natural Immunity Oncogenic Viruses Organ Transplantation Pathogenesis Pathway interactions Peptides Pharmacology Play Polyubiquitination Post-Translational Modification Site Post-Translational Protein Processing Process Proteins Publishing Reagent Recombinants Refractory Regulation Research Role Techniques Therapeutic Time Variant Viral Viral Load result Virus Virus Diseases Virus Replication acquired immunodeficiency antiretroviral therapy base inhibition of autophagy insight lytic replication novel novel strategies primary effusion lymphoma receptor targeted agent viral interferon regulatory factor-1 virus host interaction

项目摘要

ABSTRACT Human herpesvirus 8 (HHV-8) is a causal agent for Kaposi’s sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman’s disease that are often associated with acquired immunodeficiency syndrome. HHV-8 lytic replication, in addition to latency, is important for maintaining viral load within the host as well as for related pathogenesis. Recent evidence shows that HHV-8-encoded viral interferon regulatory factor 1 (vIRF-1) plays an important role in promoting virus replication by suppressing apoptosis and innate immunity elicited by infection of host cells. We recently found, for the first time, that vIRF-1 localizes to mitochondria via a novel mechanism upon virus replication and mitochondria-localized vIRF-1 is essential for successful virus replication. However, the functional significance of mitochondria-localized vIRF-1 to HHV-8 biology and pathogenesis remains to be determined. Our preliminary results showed that mitochondrial content is reduced in lytic vIRF-1-positive PEL cells but restored by pharmacological inhibition of autophagy and mitophagy. Moreover, using recombinant HHV- 8 encoding vIRF-1 with impaired mitochondria targeting and a vIRF-1-derived peptide corresponding to the mitochondrial targeting region, we demonstrated that mitochondria targeting of vIRF-1 plays an important role in regulation of mitochondria content and apoptosis during HHV-8 replication. Our further studies revealed that vIRF- 1 interacts with autophagy-related proteins (GEC1 and EF-Tu) and is subject to posttranslational modifications (caspase-5-mediated cleavage and K63-linked polyubiquitination) upon HHV-8 replication and mitochondrial damage. Moreover, inhibition of mitophagy by Mdivi-1 enhances MAVS-mediated apoptosis induced by virus replication and inhibits HHV-8 productive replication. Based on these findings, we hypothesize that vIRF-1 can sense and respond to mitochondria damage induced by HHV-8 replication and promote removal of dysfunctional mitochondria by activating mitophagy, resulting in inhibition of mitochondria-mediated antiviral responses and promotion of HHV-8 replication. Therefore, an approach to interfere with vIRF-1-activated mitophagy could lead to the development of novel antiviral agents. To further define the mechanisms and functional significance of vIRF-1- activated mitophagy in HHV-8 replication, we propose to: 1) delineate the molecular mechanism(s) of vIRF-1- mediated mitophagy activated by HHV-8 replication, 2) determine the significance to mitophagy regulation of novel posttranslational modifications of mitochondria-localized vIRF-1, and 3) determine the functional significance of vIRF-1-activated mitophagy in MAVS regulation and HHV-8 biology. Successful completion of the studies in this application will delineate the molecular interactions and processes involved in vIRF-1-acitvated mitophagy and provide evidence for the antiviral and therapeutic potentials of mitophagy inhibition. Overall, this proposal will identify a novel paradigm of virus-host interaction via mitochondria and could potentially provide a basis for future development of antiviral agents targeting mitophagy-associated interactions of vIRF-1.

摘要人类疱疹病毒8（HHV-8）是卡波西肉瘤、原发性渗出性淋巴瘤（PEL）和多中心Castleman病通常与获得性免疫缺陷综合征有关。HHV-8 除了潜伏期外，裂解性复制对于维持宿主内的病毒载量以及相关的免疫应答也是重要的。发病机制最近的证据表明，HHV-8编码的病毒干扰素调节因子1（vIRF-1）在HHV-8感染中起重要作用。在通过抑制细胞凋亡和由感染引起的先天性免疫来促进病毒复制中的重要作用宿主细胞我们最近首次发现，vIRF-1通过一种新的机制定位于线粒体，病毒复制和位于大肠杆菌中的vIRF-1对于成功的病毒复制至关重要。但 HHV-8生物学和发病机制中的VIRF-1的功能意义仍有待进一步研究。测定我们的初步结果表明，在裂解性vIRF-1阳性的PEL中，细胞，但通过药理学抑制自噬和线粒体自噬恢复。此外，使用重组HHV- 8编码线粒体靶向受损的vIRF-1和对应于该蛋白的vIRF-1衍生肽。线粒体靶向区域，我们证明了线粒体靶向vIRF-1在 HHV-8复制过程中线粒体含量和细胞凋亡的调节。我们的进一步研究表明，vIRF- 1与自噬相关蛋白（GEC 1和EF-Tu）相互作用，并进行翻译后修饰（caspase-5介导的切割和K63连接的多聚泛素化）对HHV-8复制和线粒体损害此外，Mdivi-1对线粒体自噬的抑制增强了病毒诱导的MAVS介导的细胞凋亡。复制并抑制HHV-8生产性复制。基于这些发现，我们假设vIRF-1可以对HHV-8复制诱导的线粒体损伤进行感知和应答，并促进功能失调的通过激活线粒体自噬，抑制线粒体介导的抗病毒反应，促进HHV-8复制。因此，干扰vIRF-1激活的线粒体自噬的方法可能导致新型抗病毒剂的开发。为了进一步阐明vIRF-1的作用机制和功能意义，在HHV-8复制中激活的线粒体自噬，我们提出：1）描述vIRF-1的分子机制， HHV-8复制激活的介导的线粒体自噬，2）确定新的翻译后修饰的vIRF-1，和3）确定的功能 vIRF-1激活线粒体自噬在MAVS调节和HHV-8生物学中的意义。成功完成本申请中的研究将描述vIRF-1激活的并为线粒体自噬抑制的抗病毒和治疗潜力提供证据。总体而言，这该提案将确定一种通过线粒体进行病毒-宿主相互作用的新模式，并可能提供一种为将来开发靶向vIRF-1的线粒体自噬相关相互作用的抗病毒剂奠定了基础。