Elucidating the mechanism by which ADAR1 prevents autoimmunity against self RNA
阐明 ADAR1 预防针对自身 RNA 的自身免疫的机制
基本信息
- 批准号:10667182
- 负责人:
- 金额:$ 25.43万
- 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:2023-02-08 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdenosineApoptoticAutoimmune DiseasesAutoimmunityBindingBiological ProcessBiologyBiteCalibrationCell DeathCell Death InductionCell Differentiation processCell LineCell SurvivalCellsClustered Regularly Interspaced Short Palindromic RepeatsCo-ImmunoprecipitationsDouble-Stranded RNAEnzymesFaceFoundationsFutureGene ExpressionGenesGenetic TranscriptionGenomeGoalsGrantHumanImmune responseImmune systemInfectionInnate Immune ResponseInosineInterferon Type IInterferonsIntronsInvestigationKnock-outKnowledgeLibrariesLinkMalignant NeoplasmsMedicalMessenger RNAModelingModificationMolecularMutationNamesNucleic AcidsPathway interactionsPatternPattern recognition receptorPredispositionProductionProtein FamilyProteinsRNARNA EditingRNA-Binding ProteinsReportingResearchRetroelementsRoleSmall Interfering RNAStructureTestingTissuesTranscriptTranslational RepressionUntranslated RNAUntranslated RegionsUp-RegulationViralVirusWorkautoinflammatory diseasesbasecancer cellcancer immunotherapycancer therapycrosslinking and immunoprecipitation sequencingdsRNA adenosine deaminasegenome-widehuman pluripotent stem cellinsightknock-downmelanomaneoplastic cellnovelpathogenpreventpromoterprotein kinase Rpseudotoxoplasmosis syndromereceptorreconstitutionresponseviral RNA
项目摘要
Project Summary/Abstract
To prevent or limit infection, upon sensing foreign nucleic acids (e.g., viral RNA) interferon (IFN) is produced and
elicits a potent innate immune response orchestrated by hundreds of IFN-stimulated genes. However, cells face
several challenges when attempting to differentiate between foreign and self nucleic acids. For instance, cells
often produce double-stranded RNAs (dsRNA) that can be mistakenly recognized as foreign and lead to
autoimmunity. This is exemplified by the fact that naturally occurring mutations in an RNA-editing enzyme called
ADAR1 (adenosine deaminase acting on RNA 1) cause an autoinflammatory disorder named Aicardi-Goutières
syndrome characterized by an aberrant IFN response in the absence of infection. In addition to this link to
autoimmunity, recent studies have demonstrated that depleting ADAR1 sensitizes tumor cells to innate or
therapy-induced immune responses and ADAR1 may therefore be a promising target for anti-cancer therapies.
Unfortunately, there is a gap in our basic understanding of how ADAR1 enables cells to differentiate self from
non-self RNAs. With this grant, we aim to address this knowledge gap.
ADAR1 belongs to a family of proteins that modifies adenosines (A) to inosines (I) on dsRNA. These A-
to-I modifications, through an unknown mechanism, prevent the sensing of dsRNAs by receptor proteins
including PKR (protein kinase R), which normally triggers translational inhibition and cell death. It has been
speculated that these modifications alter the secondary structures of dsRNAs and prevent them from activating
PKR. However, ADAR1 frequently targets unpaired adenosine bases, and therefore A-to-I conversion is unlikely
to cause major disruption to dsRNA structures. Here, we propose a novel hypothesis that one or more unknown
RNA-binding proteins (RBPs) are involved in differentiating ADAR1-edited vs. unedited dsRNAs. This RBP may
preferentially bind to inosine-containing RNAs and prevent them from activating PKR.
We will use a combination of genome-wide and high-coverage RBP-targeted CRISPR knockout screens
to identify protein factors, which together with ADAR1, prevent self RNA from triggering immune responses and
cell death. We will evaluate potential hits using a semi-arrayed siRNA library and include additional readouts
such as PKR activation and IFN production to prioritize candidates for further investigation. Lastly, we will initiate
preliminary mechanistic studies to determine their RNA interactions and potential protein interactions with
ADAR1 and PKR. This work will lay the foundation for future detailed mechanistic studies.
In conclusion, our proposal has the potential to open new avenues of research to understand the
biological functions and importance of inosines within RNA. Our study may reveal novel and paradigm-shifting
mechanistic insights into how cells differentiate self vs. non-self RNA. It will also provide critical information for
developing ADAR1-based cancer immunotherapies.
项目总结/摘要
为了防止或限制感染,在感测外源核酸(例如,产生病毒RNA)干扰素(IFN),
激发由数百个IFN刺激基因协调的强有力的先天免疫应答。然而,细胞面对
当试图区分外来和自身核酸时,存在几个挑战。例如,细胞
通常会产生双链RNA(dsRNA),这些RNA可能被错误地识别为外源RNA,
自身免疫这一点可以通过以下事实来证明,即在一种称为RNA编辑酶的天然突变中,
ADAR 1(腺苷脱氨酶作用于RNA 1)导致称为Aicardi-Goutières的自身炎症性疾病
在没有感染的情况下以干扰素异常反应为特征的综合征。除了此链接,
自身免疫,最近的研究表明,耗尽ADAR 1使肿瘤细胞对先天性或
因此,治疗诱导的免疫应答和ADAR 1可能是抗癌治疗的有希望的靶点。
不幸的是,我们对ADAR 1如何使细胞能够自我区分的基本理解存在差距。
非自身RNA。通过这笔赠款,我们的目标是解决这一知识差距。
ADAR 1属于将dsRNA上的腺苷(A)修饰为肌苷(I)的蛋白质家族。这些A-
通过一种未知的机制,to-I修饰阻止了受体蛋白对dsRNA的感知
包括PKR(蛋白激酶R),其通常触发翻译抑制和细胞死亡。已经
推测这些修饰改变了双链RNA的二级结构,并阻止它们激活
PKR。然而,ADAR 1经常靶向未配对的腺苷碱基,因此不太可能将A转化为I
对dsRNA结构造成重大破坏。在这里,我们提出了一个新的假设,一个或多个未知的
RNA结合蛋白(RBP)参与区分ADAR 1编辑的dsRNA与未编辑的dsRNA。该RBP可以
优先与含肌苷的RNA结合并阻止它们激活PKR。
我们将使用全基因组和高覆盖率RBP靶向CRISPR敲除筛选的组合
鉴定与ADAR 1一起阻止自身RNA触发免疫反应的蛋白质因子,
细胞死亡我们将使用半阵列siRNA文库评估潜在的命中,并包括额外的读数。
例如PKR激活和IFN产生,以优先考虑进一步研究的候选者。最后,我们将启动
初步的机制研究,以确定它们的RNA相互作用和潜在的蛋白质相互作用,
ADAR 1和PKR。这项工作将为今后详细的机理研究奠定基础。
总之,我们的建议有可能开辟新的研究途径,以了解
RNA内肌苷的生物学功能和重要性。我们的研究可能会揭示新的和范式转变
对细胞如何区分自我与非自我RNA的机械见解。它还将提供关键信息,
开发基于ADAR 1的癌症免疫疗法。
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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Charles M Rice其他文献
The antiviral state of the cell: lessons from SARS-CoV-2
细胞的抗病毒状态:来自 SARS-CoV-2 的教训
- DOI:
10.1016/j.coi.2024.102426 - 发表时间:
2024-04-01 - 期刊:
- 影响因子:5.800
- 作者:
Jérémie Le Pen;Charles M Rice - 通讯作者:
Charles M Rice
Locking out hepatitis C
锁定丙型肝炎
- DOI:
10.1038/nm0511-542 - 发表时间:
2011-05-05 - 期刊:
- 影响因子:50.000
- 作者:
Gisa Gerold;Charles M Rice - 通讯作者:
Charles M Rice
Charles M Rice的其他文献
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{{ truncateString('Charles M Rice', 18)}}的其他基金
Employing viruses to unravel the functional significance of the m5C epitranscriptome
利用病毒揭示 m5C 表观转录组的功能意义
- 批准号:
10638533 - 财政年份:2023
- 资助金额:
$ 25.43万 - 项目类别:
Tracking SARS-CoV-2 one molecule at a time: Spatiotemporal investigation of coronavirus replication dynamics and host response in single cells in vitro and in vivo
一次跟踪一个分子 SARS-CoV-2:体外和体内单细胞中冠状病毒复制动态和宿主反应的时空研究
- 批准号:
10446423 - 财政年份:2022
- 资助金额:
$ 25.43万 - 项目类别:
A clear view of encephalitis: a single cell approach to determine the basis of flaviviral pathogenesis in the central nervous system
脑炎的清晰认识:用单细胞方法确定中枢神经系统黄病毒发病机制的基础
- 批准号:
10553697 - 财政年份:2022
- 资助金额:
$ 25.43万 - 项目类别:
Tracking SARS-CoV-2 one molecule at a time: Spatiotemporal investigation of coronavirus replication dynamics and host response in single cells in vitro and in vivo
一次跟踪一个分子 SARS-CoV-2:体外和体内单细胞中冠状病毒复制动态和宿主反应的时空研究
- 批准号:
10570297 - 财政年份:2022
- 资助金额:
$ 25.43万 - 项目类别:
Scientific Core: BSL3 Virology and Animal Models
科学核心:BSL3 病毒学和动物模型
- 批准号:
10327991 - 财政年份:2022
- 资助金额:
$ 25.43万 - 项目类别:
Scientific Core: BSL3 Virology and Animal Models
科学核心:BSL3 病毒学和动物模型
- 批准号:
10841239 - 财政年份:2022
- 资助金额:
$ 25.43万 - 项目类别:
A clear view of encephalitis: a single cell approach to determine the basis of flaviviral pathogenesis in the central nervous system
脑炎的清晰认识:用单细胞方法确定中枢神经系统黄病毒发病机制的基础
- 批准号:
10446620 - 财政年份:2022
- 资助金额:
$ 25.43万 - 项目类别:
TMEM41B: a pan-flavivirus and pan-coronavirus host factor with antiviral potential
TMEM41B:具有抗病毒潜力的泛黄病毒和泛冠状病毒宿主因子
- 批准号:
10587597 - 财政年份:2022
- 资助金额:
$ 25.43万 - 项目类别:
TMEM41B: a pan-flavivirus and pan-coronavirus host factor with antiviral potential
TMEM41B:具有抗病毒潜力的泛黄病毒和泛冠状病毒宿主因子
- 批准号:
10707260 - 财政年份:2022
- 资助金额:
$ 25.43万 - 项目类别:
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