Defining the role of Host Hsp70 Subnetworks in Dengue Virus Replication
定义主机 Hsp70 子网在登革热病毒复制中的作用
基本信息
- 批准号:9215112
- 负责人:
- 金额:$ 44.55万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-11-14 至 2021-10-31
- 项目状态:已结题
- 来源:
- 关键词:ATP HydrolysisATP phosphohydrolaseAlpha CellAntiviral AgentsAntiviral TherapyArbovirusesBindingBinding ProteinsBiochemicalBiologicalBiological AssayBiologyCapsidCellsCellular biologyChemicalsCleaved cellComplexDataDengue InfectionDengue VirusDependenceDissociationEnzymesFamilyFlavivirusGenesGeneticGenomeGenomicsGoalsGuanine Nucleotide Exchange FactorsHumanHydrolysisImmunityImmunofluorescence ImmunologicInterventionKnowledgeLife Cycle StagesLocationMediatingMembrane ProteinsMolecularMolecular ChaperonesNucleotidesPeptide HydrolasesPharmacologyPlayPolyproteinsPopulations at RiskProcessProductionProtein IsoformsProteinsProteomicsProthrombinQuality ControlRNARNA VirusesRNA chemical synthesisRNA replicationRecruitment ActivityRegulationReportingResolutionRoleSpecific qualifier valueSpecificityStructureSubstrate SpecificitySystemTailTick-Borne Encephalitis VirusTick-Borne Encephalitis VirusesToxic effectUbiquitinationViralViral GenomeViral PhysiologyViral ProteinsVirionVirusVirus DiseasesVirus ReplicationWest Nile virusWorkYellow fever viruschaperone machinerycofactorexperimental studyheat-shock proteins 40inhibitor/antagonistinsightknock-downnovelparticlepathogenpreventprotein degradationprotein foldingprotein functionproteostasisviral RNA
项目摘要
Defining the role of Host Hsp70 Subnetworks in Dengue Virus Replication
Abstract: Viral protein folding and homeostasis depends entirely on the machinery of the host cell. Here we
define the dependence of Dengue virus (DENV) on the complex network of Hsp70 chaperones and
cochaperones which mediate distinct steps of the virus life cycle. We find that several cytosolic Hsp70 isoforms
are required at multiple steps of the viral life cycle to prevent viral protein degradation, promote virion assembly
and support viral enzyme function. At each step, Hsp70 function is specified by distinct subnetworks of
cofactors, called DnaJs and NEFs, that modulate Hsp70 action and localization at each step. We
hypothesize that combinations of DnaJs and NEFs dictate the specific cellular locations, substrate
specificities and downstream effectors of Hsp70 in viral replication. We propose to define the mechanism
and function of Hsp70 subnetworks in DENV replication through the integration of genetic and proteomic
analyses with biochemical and cell biological experiments. Specifically we propose to: (1) Define the
mechanism and function of DnaJs in DENV replication; (2) Dissect the role and mechanism of Hsp70
NEFs in DENV replication and (3) Define the mechanism of restriction by the Bag6-centered network.
Defining the chaperone subnetworks required for distinct steps of DENV replication will provide new insights
into key aspects of the cell biology and molecular mechanism of viral infection. Importantly, Hsp70 provides a
susceptible node for antiviral drugs, since compounds inhibiting the Hsp70 cycle blocks DENV infection with
negligible toxicity to the host. Our work will thus identify novel targets for pharmacological antiviral intervention
and uncover unanticipated cellular mechanisms for viral restriction.
确定主机Hsp70子网在登革病毒复制中的作用
摘要:病毒蛋白的折叠和动态平衡完全依赖于宿主细胞的机制。在这里我们
确定登革病毒(DENV)对Hsp70伴侣和Hsp70的复杂网络的依赖性
辅助伴侣调节病毒生命周期的不同步骤。我们发现胞质中的几种Hsp70亚型
在病毒生命周期的多个阶段都需要,以防止病毒蛋白降解,促进病毒粒子组装
并支持病毒的酶功能。在每个步骤中,Hsp70功能由不同的子网络指定
辅助因子,称为DNAJ和NEF,在每一步调节Hsp70的作用和定位。我们
假设DNAJ和NEF的组合决定了特定的细胞位置、底物
Hsp70在病毒复制中的特异性和下游效应。我们建议对该机制进行定义
以及Hsp70亚网络在DENV复制中的作用
结合生化和细胞生物学实验进行分析。具体来说,我们建议:(1)界定
Dna Js在DENV复制中的机制和作用;(2)剖析Hsp70的作用和机制
DENV复制中的Nef和(3)定义了以Bag6为中心的网络的限制机制。
定义DENV复制的不同步骤所需的守护器子网络将提供新的见解
病毒感染的细胞生物学和分子机制的关键方面。重要的是,Hsp70提供了一个
对抗病毒药物敏感的结节,因为抑制Hsp70循环的化合物通过
对寄主的毒性可以忽略不计。因此,我们的工作将确定药物抗病毒干预的新靶点
并揭示病毒限制的意想不到的细胞机制。
项目成果
期刊论文数量(0)
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JUDITH FRYDMAN其他文献
JUDITH FRYDMAN的其他文献
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{{ truncateString('JUDITH FRYDMAN', 18)}}的其他基金
Building a Toolbox of Sensors and Approaches to Monitor the Proteostasis Network Core B
构建监测蛋白质稳态网络核心 B 的传感器和方法工具箱
- 批准号:
10432028 - 财政年份:2018
- 资助金额:
$ 44.55万 - 项目类别:
Dissecting the aging-associated decline in cellular proteostasis - Project 1
剖析与衰老相关的细胞蛋白质稳态下降 - 项目 1
- 批准号:
10432032 - 财政年份:2018
- 资助金额:
$ 44.55万 - 项目类别:
Dissecting the aging-associated decline in cellular proteostasis - Project 1
剖析与衰老相关的细胞蛋白质稳态下降 - 项目 1
- 批准号:
10183114 - 财政年份:2018
- 资助金额:
$ 44.55万 - 项目类别:
Building a Toolbox of Sensors and Approaches to Monitor the Proteostasis Network Core B
构建监测蛋白质稳态网络核心 B 的传感器和方法工具箱
- 批准号:
10183111 - 财政年份:2018
- 资助金额:
$ 44.55万 - 项目类别:
Defining the role of Host Hsp70 Subnetworks in Dengue Virus Replication
定义主机 Hsp70 子网在登革热病毒复制中的作用
- 批准号:
10054971 - 财政年份:2016
- 资助金额:
$ 44.55万 - 项目类别:
2013 Stress Proteins in Growth, Development & Disease Gordon Research Conference
2013 生长、发育中的应激蛋白
- 批准号:
8597489 - 财政年份:2013
- 资助金额:
$ 44.55万 - 项目类别:
2011 Stress Proteins in Growth, Development and Disease GRC
2011 生长、发育和疾病 GRC 中的应激蛋白
- 批准号:
8193579 - 财政年份:2011
- 资助金额:
$ 44.55万 - 项目类别: