Mechanisms of HIV-1 RNA Methylation in Regulating Viral Replication
Mechanisms of HIV-1 RNA Methylation in Regulating Viral Replication
批准号:
9315991
负责人:
Li Wu
金额:
$40.03万
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
项目状态:
已结题
起止时间:
2016-08-01 至 2017-07-31
关键词:
AIDS/HIV problemAcquired Immunodeficiency SyndromeAdenosineAffectAreaB-LymphocytesBindingBinding ProteinsBinding SitesBiologyCD4 Positive T LymphocytesCell LineCell ProliferationCellsCessation of lifeCommunicable DiseasesComplexDataDevelopmentFrequenciesGene ExpressionGoalsHIV-1InfectionMapsMediatingMessenger RNAMethyltransferaseModificationPost-Transcriptional RegulationProductionProtein BiosynthesisProtein FamilyProteinsRNARNA BindingRNA SplicingRNA StabilityRNA methylationRNA replicationReaderRegulationRoleSiteStagingTestingTranslationsViralViral Reverse TranscriptionVirionVirusVirus DiseasesVirus Replicationabstractingbasegag Gene Productsgenetic regulatory proteingenomic RNAinhibitor/antagonistinsightknock-downmRNA Expressionmutantnoveloverexpressionpromotertherapeutic developmenttraffickingviral RNA
中文摘要
项目总结/摘要
这项新的R 01提案的目标是研究N6-
甲基腺苷(m6 A)修饰的HIV-1 RNA在病毒感染。内部M6 A
细胞RNA的修饰是一种新出现的转录后调控机制,
基因表达,其由三组宿主蛋白协同调节,包括
腺苷甲基转移酶(writers)、m6 A脱甲基酶(erasers)和m6 A选择性-
结合蛋白(阅读器)。m6 A修饰的细胞RNA与读取器YTH结构域的结合
家族蛋白(YTHDF 1、2和3)可显著影响RNA功能的各个方面
在翻译过程中。然而,尚不清楚HIV-1 RNA是否含有m6 A修饰,
该修饰是否调节CD 4 + T细胞中的病毒复制。
我们最近在HIV-1基因组RNA(gRNA)中发现了多个m6 A修饰区域。
在HIV-1感染的细胞中被阅读器(YTHDF 1 -3蛋白)结合。我们的数据显示,
阅读者的表达水平可显著调节HIV-1感染后靶细胞的表达水平,
细胞此外,在病毒生产细胞中敲除m6 A写入器或擦除器显著地降低了病毒的产量。
影响HIV-1 Gag蛋白合成和病毒释放,表明m6 A的重要性
HIV-1 RNA在病毒生产中的修饰。因此,我们假设,m6 A修饰
HIV-1 RNA通过m6 A阅读器、写入器和橡皮擦来调节细胞中的病毒复制,
这可能对HIV-1生命周期的不同阶段产生消极或积极的影响。我们将
主要使用原代CD 4 + T细胞在三个特定目标中检验总体假设。目标1.到
研究HIV-1 RNA m6 A修饰在病毒感染中的作用以及m6 A的机制
阅读器介导的病毒抑制;目的2.研究m6 A的作用和机制
调节HIV-1感染的作家;目标3。探讨了在体外培养条件下,
m6 A擦除器调节HIV-1感染。
总体影响:完成这些拟议的研究将揭示新的作用,
HIV-1 RNA的m6 A修饰在调节细胞中病毒感染中的机制。研究
HIV-1 RNA的m6 A修饰及其与宿主蛋白的相互作用代表了一个新的研究领域。
HIV-1 RNA生物学,可以促进针对HIV-1感染的治疗开发。
英文摘要
Project Summary/Abstract
The goal of this new R01 proposal is to investigate the novel role and mechanisms of N6-
methyladenosine (m6A) modification of HIV-1 RNA in viral infection. The internal m6A
modification of cellular RNA is a newly emerging mechanism of post-transcriptional control of
gene expression, which is coordinately regulated by three groups of host proteins, including
adenosine methyltransferases (writers), m6A demethylases (erasers), and m6A-selective-
binding proteins (readers). Binding of m6A-modified cellular RNA by the readers, YTH domain
family proteins (YTHDF1, 2, and 3), can significantly affect various aspects of RNA functions
during translation. However, it is unknown whether HIV-1 RNA contains m6A modification and
whether the modification regulates viral replication in CD4+ T-cells.
We recently identified multiple regions of m6A modification in HIV-1 genomic RNA (gRNA)
bound by the readers (YTHDF1-3 proteins) in HIV-1-infected cells. Our data showed that the
expression levels of the readers can significantly modulated HIV-1 postentry infection in target
cells. Moreover, knockdown of the m6A writers or an eraser in virus producer cells significantly
affected HIV-1 Gag protein synthesis and viral release, suggesting the importance of m6A
modification of HIV-1 RNA in viral production. Thus, we hypothesize that m6A modification of
HIV-1 RNA regulates viral replication in cells by engaging the m6A readers, writers, and erasers,
which can have negative or positive impacts on different stages of the HIV-1 lifecycle. We will
test the overall hypothesis in three specific aims mainly using primary CD4+ T-cells. Aim 1. To
examine the role of HIV-1 RNA m6A modification in viral infection and the mechanisms of m6A
reader-mediated viral inhibition; Aim 2. To investigate the role and mechanisms of the m6A
writers in regulating HIV-1 infection; and Aim 3. To investigate the role and mechanisms of the
m6A erasers in regulating HIV-1 infection.
Overall impact: Accomplishing these proposed studies will reveal the novel role and
mechanisms of m6A modification of HIV-1 RNA in regulating viral infection in cells. Studying the
m6A modification of HIV-1 RNA and its interactions with host proteins represents a new area of
HIV-1 RNA biology, which can facilitate therapeutic development against HIV-1 infection.
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