Role of Host Filamin Proteins in Regulating Filovirus Entry and Egress
宿主细丝蛋白在调节丝状病毒进入和排出中的作用
基本信息
- 批准号:10644499
- 负责人:
- 金额:$ 26.83万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-03-10 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:ActinsAffectAntibody TherapyAntiviral TherapyBAG3 geneBiochemicalBiological AssayCell FractionationCell SeparationCell divisionCell membraneCell physiologyCellsCellular MorphologyCessation of lifeComplexCytokinesisDevelopmentDisease OutbreaksEbolaEbola virusEyeFamilyFilopodiaFilovirusFutureGoalsHIV-1Host Defense MechanismHumanImmunologicsInfectionIntegrinsLaboratoriesLife Cycle StagesLinkLiquid substanceMagnetismMammalian CellMarburgvirusMediatingMembraneMicroscopyMolecularPathway interactionsProcessProteinsProteomeReagentRecombinantsRegulationRibonucleasesRoleSeminal fluidSiteSmall Interfering RNATestingTherapeutic InterventionTotal Internal Reflection FluorescentVesicleVesicular stomatitis Indiana virusViralViral Hemorrhagic FeversVirionVirusVirus AssemblyVirus DiseasesVirus ReplicationZoonosescell motilitychronic infectioncombatconfocal imagingcrosslinkdriving forceemerging pathogenextracellularfilamininsightlink proteinlong-term sequelaemembernonhuman primatenovelparticleprotein crosslinktraffickingubiquitin-protein ligasevirus host interaction
项目摘要
Filoviruses (Ebola [EBOV] and Marburg [MARV]) are zoonotic, emerging pathogens that cause sporadic and
global outbreaks of severe hemorrhagic fever in humans and non-human primates. As EBOV and MARV can
establish persistent infections in the CNS, semen, eye, and other immunologically privileged sites inaccessible
to antibody therapy, and their re-emergence can result in long-term sequelae and death, understanding of host
defense mechanisms that could lead to the development of new antiviral therapies is more critical than ever. Our
lab is at the forefront of identifying host proteins that interact both physically and functionally with the filovirus
VP40 matrix protein, the driving force for virus assembly and egress, to regulate these late stages of virus
replication. To better understand the functional filovirus-host interactome, our laboratory has focused on direct
interactions between the PPxY Late (L) domain motif conserved in the VP40 proteins of EBOV (eVP40) and
MARV (mVP40) and modular WW-domains from select host proteins. In addition to positive regulators of filovirus
egress, we have recently identified WW-domain interactors that negatively regulate VP40-mediated budding,
including YAP/TAZ, BAG3, and WWOX. While the impact of these negative regulators is likely multifactorial and
complex, we have made the intriguing observation that filamin B, a common downstream effector of YAP/TAZ
and BAG3, acts as a potential dual regulator of live EBOV/MARV infectivity/entry and live EBOV/MARV egress.
As dual role regulation of key stages at opposite ends of the filovirus lifecycle is novel and unexpected, the
ultimate goal of this proposal is to determine how host protein filamin B mechanistically impacts the filovirus
lifecycle. Filamins are a family of actin crosslinking/stabilizing proteins that regulate actin dynamics at the plasma
membrane to control cell migration and morphology, vesicle trafficking, macropinocytosis, and cell division.
Notably, macropinocytosis
macropinosomes
is
(MPs) that are densely coated with actin, filamin, and filamin-associated proteins
a key entry pathway for filoviruses, as these viruses enter the cell in vesicles
termed
. In addition,
filamins are linked to cellular processes that mimic virion formation and/or egress such as filopodia formation,
cell migration, and cytokinesis. Thus, we hypothesize that filamin B regulates infectivity/entry of filoviruses
through effects on macropinocytosis, and regulates filovirus budding through effects on egress of filopodia-like
filovirus particles. In this exploratory proposal, we propose to investigate the mechanisms by which filamin
regulates filovirus infectivity/entry (Aim 1) and egress (Aim 2). Results from these studies will impact the field by
identifying a novel host protein(s) whose expression modulates two critical and opposite steps in the filovirus
lifecycle; entry and exit, as well as providing a better fundamental understanding of the functional filovirus-host
interactome and host defense mechanisms that could lead to the development of new antiviral therapies.
丝状病毒(埃博拉[EBOV]和马尔堡[MARV])是人畜共患的、新出现的病原体,其引起散发性和
在人类和非人类灵长类动物中爆发严重出血热。EBOV和MARV可以
在中枢神经系统、精液、眼睛和其他免疫特权部位建立持续感染
抗体治疗,其重新出现可能导致长期后遗症和死亡,了解宿主
可能导致新的抗病毒疗法发展的防御机制比以往任何时候都更加重要。我们
该实验室处于鉴定与丝状病毒在物理和功能上相互作用的宿主蛋白质的最前沿
VP 40基质蛋白是病毒组装和排出的驱动力,用于调节病毒的这些晚期阶段,
复制的为了更好地了解丝状病毒-宿主相互作用组的功能,我们的实验室专注于直接
EBOV的VP 40蛋白(eVP 40)中保守的PPxY Late(L)结构域基序与
MARV(mVP 40)和来自选择的宿主蛋白的模块化的WW-domain。除了丝状病毒的正调控因子外
出口,我们最近已经确定了负调控VP 40介导的出芽,
包括雅普/TAZ、BAG 3和WWOX。虽然这些负面调节剂的影响可能是多因素的,
复杂,我们已经作出了有趣的观察,细丝蛋白B,一个共同的下游效应的雅普/TAZ
和BAG 3,作为活EBOV/MARV感染性/进入和活EBOV/MARV排出的潜在双重调节剂。
由于丝状病毒生命周期的相对两端的关键阶段的双重作用调节是新颖且出乎意料的,因此,
本研究的最终目标是确定宿主蛋白细丝蛋白B是如何影响丝状病毒的
生命周期丝状蛋白是一个肌动蛋白交联/稳定蛋白家族,其调节血浆中的肌动蛋白动力学
膜,以控制细胞迁移和形态、囊泡运输、巨胞饮和细胞分裂。
值得注意的是,
大胞饮体
是
(MPs)它们被肌动蛋白、细丝蛋白和细丝蛋白相关的蛋白质所覆盖
丝状病毒进入细胞的关键途径,因为这些病毒以囊泡形式进入细胞
称为
.此外,本发明还提供了一种方法,
丝状体与模拟病毒体形成和/或排出的细胞过程如丝状伪足形成有关,
细胞迁移和胞质分裂。因此,我们假设细丝蛋白B调节丝状病毒的感染性/进入
通过影响巨胞饮作用,并通过影响丝状伪足样病毒的排出来调节丝状病毒出芽
丝状病毒颗粒。在这个探索性的建议中,我们建议研究细丝蛋白
调节丝状病毒的感染性/进入(Aim 1)和排出(Aim 2)。这些研究的结果将影响该领域,
鉴定其表达调节丝状病毒中两个关键且相反的步骤的新宿主蛋白
生命周期;进入和退出,以及提供对功能性丝状病毒宿主的更好的基本理解
相互作用体和宿主防御机制,可能导致新的抗病毒疗法的发展。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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RONALD N HARTY其他文献
RONALD N HARTY的其他文献
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{{ truncateString('RONALD N HARTY', 18)}}的其他基金
Development of Host- Oriented Therapeutics Targeting Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2),
针对严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 的面向宿主的疗法的开发,
- 批准号:
10688262 - 财政年份:2022
- 资助金额:
$ 26.83万 - 项目类别:
Development of Host- Oriented Therapeutics Targeting Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2),
针对严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 的面向宿主的疗法的开发,
- 批准号:
10545109 - 财政年份:2022
- 资助金额:
$ 26.83万 - 项目类别:
Role of Host Angiomotin as a Central Regulator of Filovirus Egress and Dissemination
宿主血管动蛋白作为丝状病毒排出和传播的中央调节剂的作用
- 批准号:
10380684 - 财政年份:2021
- 资助金额:
$ 26.83万 - 项目类别:
Role of Host Angiomotin as a Central Regulator of Filovirus Egress and Dissemination
宿主血管动蛋白作为丝状病毒排出和传播的中央调节剂的作用
- 批准号:
10217843 - 财政年份:2021
- 资助金额:
$ 26.83万 - 项目类别:
Modular Domains of Host Proteins Regulate Filovirus Maturation
宿主蛋白的模块化结构域调节丝状病毒成熟
- 批准号:
9517218 - 财政年份:2018
- 资助金额:
$ 26.83万 - 项目类别:
Development of Small Molecule Therapeutics Targeting Hemorrhagic Fever Viruses
针对出血热病毒的小分子疗法的开发
- 批准号:
10257889 - 财政年份:2018
- 资助金额:
$ 26.83万 - 项目类别:
Development of Small Molecule Therapeutics Targeting Hemorrhagic Fever Viruses
针对出血热病毒的小分子疗法的开发
- 批准号:
10368115 - 财政年份:2018
- 资助金额:
$ 26.83万 - 项目类别:
Development of Small Molecule Therapeutics Targeting Hemorrhagic Fever Viruses
针对出血热病毒的小分子疗法的开发
- 批准号:
10599837 - 财政年份:2018
- 资助金额:
$ 26.83万 - 项目类别:
DEVELOPMENT OF SMALL MOLECULE THERAPEUTICS AGAINST RNA VIRUSES
针对 RNA 病毒的小分子疗法的开发
- 批准号:
8903846 - 财政年份:2015
- 资助金额:
$ 26.83万 - 项目类别:
Innate Immune Regulation of Intracellular Pathways Involved in Filovirus Budding
丝状病毒出芽涉及的细胞内途径的先天免疫调节
- 批准号:
8635498 - 财政年份:2013
- 资助金额:
$ 26.83万 - 项目类别:
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