Structural and functional analyses of the RIG-I filament in innate immunity
先天免疫中 RIG-I 丝的结构和功能分析
基本信息
- 批准号:8817425
- 负责人:
- 金额:$ 43.98万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-09-17 至 2019-08-31
- 项目状态:已结题
- 来源:
- 关键词:ATP HydrolysisAffinityAntiviral AgentsAntiviral TherapyArchitectureAutoimmune ProcessBindingBinding ProteinsC-terminalCaspaseCellsCharacteristicsComplexConflict (Psychology)CytoplasmDataDefective VirusesDetectionDiseaseDouble-Stranded RNAFamilyFilamentGenesGeneticGoalsHIVHeadImmuneImmune systemImmunologic ReceptorsImmunotherapyIn VitroIndividualInflammatoryInfluenzaInfluenza A Virus, H1N1 SubtypeInterferonsKineticsLengthLigandsLinkLiteratureManuscriptsModelingMolecularNatural ImmunityNaturePathogenesisPathway interactionsPolyubiquitinPreparationProtein BindingRNARNA Recognition MotifRecruitment ActivityRegulationResearchSendai virusSevere Acute Respiratory SyndromeSignal PathwaySignal TransductionSignaling MoleculeStructureTailTestingTherapeuticTretinoinViralViral GenomeViral ProteinsVirusVirus Diseasescancer therapycell typeglobal healthhelicaseinfluenzavirusinsightmonomernovelnovel therapeuticspandemic diseaseparalogous genepreventprotein protein interactionpublic health relevancereceptorsynergismtherapeutic targetviral RNA
项目摘要
DESCRIPTION (provided by applicant): Ligand-induced receptor oligomerization is a ubiquitous mechanism for signal activation in the immune system. Understanding how these receptors oligomerize during ligand recognition and activate downstream signaling pathways is fundamental to understanding their functions and is pre-requisite to therapeutic application of these receptors. In this proposal, we describe our strategies to investigate the oligomerization mechanism, oligomer architecture and signal activation mechanism of a conserved innate immune receptor, retinoic acid inducible gene-1 (RIG-I). RIG-I and its paralog, MDA5, represent a major receptor family that recognizes viral RNAs in the cytoplasm of a broad range of cell types. RIG-I and MDA5 both contain a tandem caspase activation recruitment domain (2CARD) for signal activation and a helicase domain and a C-terminal domain for RNA binding and RNA- dependent ATP hydrolysis. 2CARDs of RIG-I and MDA5 activate their downstream adaptor molecule, MAVS, by promoting its monomer-to-filament transition. MAVS filaments, in turn, recruit further downstream signaling molecules to activate the IFN?/? signaling pathways. We have previously shown that MDA5 cooperatively forms a filament along the length of dsRNA, and that its formation is important for high affinity interaction with dsRNA, oligomerization of 2CARD and dsRNA length dependent regulation of signaling activity. Unlike MDA5, oligomerization of RIG-I has been unclear, and has been thought to strictly require a co-factor, K63-linked polyubiquitin chains. Recently, we found that RIG-I assembles into a filament during ATP hydrolysis, and that the filament can directly activate MAVS in the absence of polyubiquitin chains, suggesting a novel mechanism for RNA recognition and signal activation by RIG-I. We here propose to determine the precise mechanisms by which RIG-I assembles into a filament (Aim 1) and stimulates MAVS filament formation independent of or together with polyubiquitin chains (Aim 2), and how RIG-I filaments form and function in the context of viral infection (Aim 3). This proposal builds upon our previous research on the MDA5 filament (Wu et al, Cell, 2013; Peisley et al, PNAS, 2012 & PNAS, 2011; Rice et al, Nat. Genetics, In press), our discovery of the RIG-I filament (Peisley et al, Mol. Cell, 2013), a very recent crystal structure of RIG-I 2CARD
tetramer bound by K63-Ubn (Peisley et al, Nature, Epub) and finally the atomic structures of the MAVS filament as well as the RIG-I 2CARD:MAVS CARD complex (manuscript in preparation). We believe that the proposed research will provide a comprehensive picture of functions of RIG-I and help us dissect commonalities and divergences between RIG-I and MDA5 in viral RNA detection and signal activation mechanisms. Furthermore, detailed mechanistic understanding of the RIG-I filament could potentially offer insights into novel therapeutic strategies to modulat the activity of RIG-I in antiviral and anticancer therapies.
描述(由申请人提供):配体诱导的受体寡聚化是免疫系统中信号激活的普遍机制。了解这些受体在配体识别过程中如何寡聚化并激活下游信号传导途径是了解其功能的基础,也是这些受体治疗应用的先决条件。在这个建议中,我们描述了我们的策略,调查寡聚化机制,寡聚体结构和信号激活机制的保守的先天免疫受体,视黄酸诱导基因-1(RIG-I)。 RIG-I和它的副产物,MDA 5,代表了一个主要的受体家族,识别广泛的细胞类型的细胞质中的病毒RNA。RIG-I和MDA 5都含有用于信号激活的串联半胱天冬酶激活募集结构域(2CARD)和用于RNA结合和RNA依赖性ATP水解的解旋酶结构域和C末端结构域。2 RIG-I和MDA 5的CARD通过促进其单体到细丝的转变来激活其下游衔接子分子MAVS。反过来,MAVS丝又进一步募集下游信号分子来激活IFN?/?信号通路我们先前已经表明,MDA 5合作形成一个长丝沿着长度的dsRNA,它的形成是重要的高亲和力相互作用与dsRNA,寡聚化的2CARD和dsRNA长度依赖性调节信号传导活性。与MDA 5不同,RIG-I的寡聚化一直不清楚,并且被认为严格需要辅因子K63连接的多聚泛素链。最近,我们发现RIG-I在ATP水解过程中组装成细丝,并且细丝可以在不存在多聚泛素链的情况下直接激活MAVS,这表明RIG-I识别RNA并激活信号的新机制。 我们在这里提出,以确定RIG-I组装成细丝(目的1)和刺激MAVS细丝形成独立的或与多聚泛素链(目的2),以及如何RIG-I细丝的形成和功能的背景下,病毒感染(目的3)的确切机制。该提议基于我们先前对MDA 5细丝的研究(Wu等人,Cell,2013; Peisley等人,PNAS,2012 & PNAS,2011; Rice等人,Nat. Genetics,In press),我们对RIG-I细丝的发现(Peisley等人,Mol. Cell,2013),RIG-I 2CARD的最近晶体结构
通过K63-Ubn结合的四聚体(Peisley等,Nature,Epub)和最后的MAVS细丝以及RIG-I 2CARD:MAVS CARD复合物的原子结构(手稿在制备中)来描述。我们相信,拟议的研究将提供RIG-I功能的全面了解,并帮助我们剖析RIG-I和MDA 5在病毒RNA检测和信号激活机制方面的共性和差异。此外,RIG-I细丝的详细机制理解可能提供对新型治疗策略的见解,以调节RIG-I在抗病毒和抗癌治疗中的活性。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Sun Hur其他文献
Sun Hur的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Sun Hur', 18)}}的其他基金
Molecular mechanisms for antiviral signaling and regulation by MDA5 and TRIM65
MDA5 和 TRIM65 抗病毒信号传导和调节的分子机制
- 批准号:
10414029 - 财政年份:2020
- 资助金额:
$ 43.98万 - 项目类别:
Molecular mechanisms for antiviral signaling and regulation by MDA5 and TRIM65
MDA5 和 TRIM65 抗病毒信号传导和调节的分子机制
- 批准号:
10206037 - 财政年份:2020
- 资助金额:
$ 43.98万 - 项目类别:
Molecular mechanisms for antiviral signaling and regulation by MDA5 and TRIM65
MDA5 和 TRIM65 抗病毒信号传导和调节的分子机制
- 批准号:
10651722 - 财政年份:2020
- 资助金额:
$ 43.98万 - 项目类别:
Defining the molecular mechanism of Aire in T-cell tolerance
定义 Aire 在 T 细胞耐受中的分子机制
- 批准号:
9814890 - 财政年份:2019
- 资助金额:
$ 43.98万 - 项目类别:
Resolving functional aggregates: A new perspective on innate immune control
解决功能聚集:先天免疫控制的新视角
- 批准号:
10001442 - 财政年份:2019
- 资助金额:
$ 43.98万 - 项目类别:
Resolving functional aggregates: A new perspective on innate immune control
解决功能聚集:先天免疫控制的新视角
- 批准号:
10669648 - 财政年份:2019
- 资助金额:
$ 43.98万 - 项目类别:
Resolving functional aggregates: A new perspective on innate immune control
解决功能聚集:先天免疫控制的新视角
- 批准号:
10456170 - 财政年份:2019
- 资助金额:
$ 43.98万 - 项目类别:
Resolving functional aggregates: A new perspective on innate immune control
解决功能聚集:先天免疫控制的新视角
- 批准号:
10217977 - 财政年份:2019
- 资助金额:
$ 43.98万 - 项目类别:
Re-defining RIG-I-like helicases as viral RNA receptors with effector functions
将 RIG-I 样解旋酶重新定义为具有效应子功能的病毒 RNA 受体
- 批准号:
9296274 - 财政年份:2017
- 资助金额:
$ 43.98万 - 项目类别:
Interplays between ADAR1 and MDA5 in the pathogenesis of Aicardi-Goutière Syndrome
ADAR1 和 MDA5 在 Aicardi-Goutière 综合征发病机制中的相互作用
- 批准号:
9099769 - 财政年份:2015
- 资助金额:
$ 43.98万 - 项目类别:
相似海外基金
Construction of affinity sensors using high-speed oscillation of nanomaterials
利用纳米材料高速振荡构建亲和传感器
- 批准号:
23H01982 - 财政年份:2023
- 资助金额:
$ 43.98万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Affinity evaluation for development of polymer nanocomposites with high thermal conductivity and interfacial molecular design
高导热率聚合物纳米复合材料开发和界面分子设计的亲和力评估
- 批准号:
23KJ0116 - 财政年份:2023
- 资助金额:
$ 43.98万 - 项目类别:
Grant-in-Aid for JSPS Fellows
Development of High-Affinity and Selective Ligands as a Pharmacological Tool for the Dopamine D4 Receptor (D4R) Subtype Variants
开发高亲和力和选择性配体作为多巴胺 D4 受体 (D4R) 亚型变体的药理学工具
- 批准号:
10682794 - 财政年份:2023
- 资助金额:
$ 43.98万 - 项目类别:
Platform for the High Throughput Generation and Validation of Affinity Reagents
用于高通量生成和亲和试剂验证的平台
- 批准号:
10598276 - 财政年份:2023
- 资助金额:
$ 43.98万 - 项目类别:
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
- 批准号:
2233343 - 财政年份:2023
- 资助金额:
$ 43.98万 - 项目类别:
Standard Grant
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
- 批准号:
2233342 - 财政年份:2023
- 资助金额:
$ 43.98万 - 项目类别:
Standard Grant
Molecular mechanisms underlying high-affinity and isotype switched antibody responses
高亲和力和同种型转换抗体反应的分子机制
- 批准号:
479363 - 财政年份:2023
- 资助金额:
$ 43.98万 - 项目类别:
Operating Grants
Deconstructed T cell antigen recognition: Separation of affinity from bond lifetime
解构 T 细胞抗原识别:亲和力与键寿命的分离
- 批准号:
10681989 - 财政年份:2023
- 资助金额:
$ 43.98万 - 项目类别:
CAREER: Engineered Affinity-Based Biomaterials for Harnessing the Stem Cell Secretome
职业:基于亲和力的工程生物材料用于利用干细胞分泌组
- 批准号:
2237240 - 财政年份:2023
- 资助金额:
$ 43.98万 - 项目类别:
Continuing Grant
ADVANCE Partnership: Leveraging Intersectionality and Engineering Affinity groups in Industrial Engineering and Operations Research (LINEAGE)
ADVANCE 合作伙伴关系:利用工业工程和运筹学 (LINEAGE) 领域的交叉性和工程亲和力团体
- 批准号:
2305592 - 财政年份:2023
- 资助金额:
$ 43.98万 - 项目类别:
Continuing Grant