Role of cell polarity regulators in HIV spreading
Role of cell polarity regulators in HIV spreading
批准号:
10013784
负责人:
HEINRICH GOTTLINGER
金额:
$53.28万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-01-01 至 2024-12-31
关键词:
ActinsAntigen-Presenting CellsCD4 Positive T LymphocytesCDC42 geneCell LineCell PolarityCellsComplexCuesCytoskeletonDataDrug TargetingEukaryotic CellExocytosisFMNL1 geneFamilyFilopodiaGolgi ApparatusGuanosine Triphosphate PhosphohydrolasesHIVHIV-1HumanInfectionInvestigationKnock-outLife Cycle StagesMediatingMembraneMicrotubule-Organizing CenterMicrotubulesModelingMolecularMonomeric GTP-Binding ProteinsPAK-1 kinasePARD6A genePeripheral Blood Mononuclear CellPhosphotransferasesPolymeraseProcessProtein KinaseProteinsPublic HealthReportingRoleSecretory VesiclesSignal PathwaySiteSurfaceT-LymphocyteVesicleViralVirionVirusYeastscdc42 GTP-Binding Proteincytokineexperimental studyimmunological synapse formationinsightmanpolarized cellpolymerizationreconstitutionresponsesynaptogenesistraffickingtransmission processvirological synapse
中文摘要
摘要
HIV-1感染的T细胞可以与未感染的T细胞形成稳定的结合物,这一过程被称为“病毒学结合”。
突触形成。这一过程让人想起“免疫突触”的形成,在此期间,
CD 4 + T细胞迅速破坏肌动蛋白细胞骨架、微管组织中心(MTOC)和细胞因子-
含有朝向抗原呈递细胞的囊泡。免疫过程中CD 4 + T细胞的极化
突触的形成依赖于RHO家族的GT3 CDC 42,这是一种在突触形成中起关键作用的分子开关。
真核细胞极性的建立。
我们现在已经观察到,CDC 42对于HIV-1在几种T细胞系中的有效传播至关重要
和原代细胞中。然而,我们的数据也意味着,CDC 42是完成一个单一的,
循环复制。总之,我们的观察结果表明CDC 42参与了HIV-1的细胞间传播。
CDC 42通过效应子刺激膜延伸的形成,如丝状伪足,
介导肌动蛋白细胞骨架的极化,HIV-1可以利用丝状伪足桥从细胞中传播
到细胞。因此,我们的数据让我们提出了一个工作模型,其中CDC 42对形成
细胞间延伸,促进HIV-1在CD 4 + T细胞之间的转移。为了支持这一模式,我们
已经观察到CDC 42是MOLT-3形成HIV-1诱导的膜延伸所必需的
细胞另一种工作模式是,HIV-1病毒粒子的两极化运输需要CDC 42
病毒学突触的组成部分。
我们建议直接研究CDC 42在HIV-1细胞间传播和病毒学中的作用。
突触形成,并确定HIV-1是否调节CDC 42的活性。我们亦建议
研究CDC 42效应物在调节HIV-1局部肌动蛋白组装和极化运输中的作用
蔓延在这些效应器中,F-BAR蛋白与肌动蛋白聚合机制连接,
F-BAR蛋白PACSIN 2,我们最近发现它与HIV-1的细胞间传播有关。
值得注意的是,我们的初步结果表明,某些CDC 42效应,包括CDC 42调节的肌动蛋白,
聚合酶FMNL 1和一个控制极化胞吐作用的假定的CDC 42效应子,在
HIV-1复制。
拟议的研究有可能产生新的基本见解的机制,
重要但知之甚少的HIV-1传播方式。特别重要的是,
鉴定出CDC 42下游的激酶对HIV-1传播至关重要,因为蛋白激酶
构成了最重要的药物靶点之一。
英文摘要
ABSTRACT
HIV-1-infected T cells can form stable conjugates with non-infected T cells in a process known as “virological
synapse” formation. This process is reminiscent of the formation of an “immunological synapse”, during which
CD4+ T cells rapidly polarize the actin cytoskeleton, the microtubule-organizing center (MTOC), and cytokine-
containing vesicles towards antigen-presenting cells. The polarization of CD4+ T cells during immunological
synapse formation depends on the RHO family GTPase CDC42, a molecular switch that has a key role in the
establishment of polarity in eukaryotic cells.
We have now observed that CDC42 is critical for the efficient spreading of HIV-1 in several T cell lines
and in primary cells. However, our data also imply that CDC42 is dispensable for the completion of a single
cycle of replication. Together, our observations implicate CDC42 in the cell-to-cell transmission of HIV-1.
CDC42 stimulates the formation of membrane extensions, such as filopodia, through effectors that
mediate the polarization of the actin cytoskeleton, and HIV-1 can exploit filopodial bridges to spread from cell
to cell. Thus, our data let us to propose a working model in which CDC42 is crucial for the formation of
intercellular extensions that facilitate the transfer of HIV-1 between CD4+ T cells. In support of this model, we
have observed that CDC42 is required for the formation of HIV-1-induced membrane extensions by MOLT-3
cells. An alternative working model is that CDC42 is required for the polarized trafficking of HIV-1 virion
components to the virologic synapse.
We propose to directly examine the roles of CDC42 in HIV-1 cell-to-cell transmission and virological
synapse formation, and to determine whether HIV-1 regulates the activity of CDC42. We also propose to
examine the roles of CDC42 effectors that regulate localized actin assembly and polarized trafficking in HIV-1
spreading. Among these effectors are F-BAR proteins that connect to actin polymerization machinery, as does
the F-BAR protein PACSIN2, which we have recently implicated in the cell-to-cell transmission of HIV-1.
Notably, our preliminary results indicate that certain CDC42 effectors, including the CDC42-regulated actin
polymerase FMNL1 and a putative CDC42 effector that controls polarized exocytosis, have crucial roles in
HIV-1 replication.
The proposed studies have the potential to yield fundamental new insights into the mechanism of an
important but poorly understood mode of HIV-1 transmission. Of particular significance would be the
identification of a kinase downstream of CDC42 as being critical for HIV-1 spreading, since protein kinases
constitute one of the most important groups of drug targets.
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Role of cell polarity regulators in HIV spreading
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批准号:10541198
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项目类别:
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资助金额:$53.28万
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财政年份:2020
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负责人:HEINRICH GOTTLINGER
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依托单位:
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