Factors regulating strength and duration of STING signaling
调节 STING 信号强度和持续时间的因素
基本信息
- 批准号:10490901
- 负责人:
- 金额:$ 42.36万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-17 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:AffectAllelesAutoimmunityAutophagocytosisAutophagosomeBiochemicalBiologyCRISPR screenCell DeathCell modelCellsChronicClustered Regularly Interspaced Short Palindromic RepeatsDNADevelopmentEndosomesFactor AnalysisGenesGoalsGolgi ApparatusHereditary Spastic ParaplegiaHumanHuman PathologyIRF3 geneImmuneImmune systemImmunityInflammationInheritedInterferonsKnock-outKnowledgeLigandsLigationLysosomesMalignant NeoplasmsMediatingMitochondriaModelingMutateMutationNeuraxisNuclearOptical MethodsPathogenicityPathway interactionsPatternProcessProteinsProteomicsRegulationResolutionRoleSensorySignal TransductionSiteStimulator of Interferon GenesTBK1 geneTREX1 geneTestingTherapeuticTumor ImmunityUbiquitinationVaccinesVascular DiseasesVirusVirus DiseasesWorkdisease-causing mutationgenome-widehuman diseaseimmune activationimmune healthimprovedmutantmutation screeningneoplastic cellnovelnucleasepathogenpseudotoxoplasmosis syndromerecruitresponsesealsensortraffickingtumorubiquitin-protein ligase
项目摘要
DNA sensing by the cGAS-STING pathway is essential for recognizing pathogens, tumor cells, and mitochondrial
or nuclear DNA under certain conditions, leading to homeostatic responses, such as immune control of
pathogens and cancer. Under some conditions, such as loss of the nuclease TREX1, excess DNA triggers cGAS-
STING and causes a chronic inflammation (e.g., Aicardi Goutierès Syndrome, or a constitutively active STING
allele, causes SAVI, an inherited vasculopathy). Upon activation by its ligand, cGAMP, STING translocates from
ER → Golgi → endosomes where it signals through TBK1 and IRF3 to activate interferons, and is then degraded
via lysosomes. These trafficking patterns are central to STING’s function, and yet we lack knowledge of many of
the genes regulating these processes. To identify regulators of STING activity, trafficking and degradation, we
performed two genome-wide CRISPR knockout screens, as well as a proximity-ligation mediated proteomic
analysis, and a focused CRISPR screen. Studying the dozens of factors found, we made two significant
discoveries that provide the basis for this proposal. First, we found that ESCRT-dependent endosomal
microautophagy requires recognition of ubiquitinated STING on endosomes, and is critical for STING
degradation, autophagosome sealing and signaling regulation. Disruption of this pathway by a pathogenic
ESCRT subunit mutant (found in a human disease) leads to constitutive STING signaling at steady state.
Second, we uncovered a novel interaction of ER-localized STING with endosomal protein DNAJC13, leading to
restriction of STING ER exit and activation. Loss of DNAJC13 or disruption of ER-endosome contact sites
dramatically boosts STING activity. Having defined a model of STING ubiquitination controlling autophagy
resolution, and DNAJC13 restricting STING ER exit, we propose to further our understanding of this pathway by
studying the mechanisms underlying these processes, including identifying E3 ubiquitin ligases that modify
STING and induce ESCRT-dependent autophagy, and determining the impact of STING-induced endosomal
microautophagy on viral infections. We will also determine how DNAJC13 blocks STING activity by altering
STING trafficking. We will test the roles of DNAJC13 and ER-endosomal contacts in limiting STING activation
by restricting STING ER exit to the TGN. To define the biochemical mechanisms of STING interactions, we will
use deep mutational scanning to find motifs on STING that are responsible for interactions with DNAJC13 and
for the effects of DNAJC13 on STING trafficking, as well as motifs that control other aspects of STING localization
and signaling. Finally, we will study how mutations in genes involved in human pathologies that regulate STING
trafficking, impact inflammation and death of cells of the central nervous system. A better understanding of
STING trafficking, degradation and signaling will help us develop therapeutic approaches to dampen
autoimmunity or boost pathogen and tumor immunity.
cGAS-STING 通路的 DNA 传感对于识别病原体、肿瘤细胞和线粒体至关重要
或核DNA在某些条件下,导致稳态反应,例如免疫控制
病原体和癌症。在某些条件下,例如核酸酶 TREX1 丢失,过量 DNA 会触发 cGAS-
STING 并引起慢性炎症(例如,Aicardi Goutierès 综合征,或持续活跃的 STING)
等位基因,导致 SAVI(一种遗传性血管病)。被其配体 cGAMP 激活后,STING 从
ER → 高尔基体 → 内体,通过 TBK1 和 IRF3 发出信号以激活干扰素,然后被降解
通过溶酶体。这些贩运模式是 STING 功能的核心,但我们对许多方面缺乏了解
调节这些过程的基因。为了确定 STING 活动、贩运和降解的监管者,我们
进行了两次全基因组 CRISPR 敲除筛选,以及邻近连接介导的蛋白质组学
分析和重点 CRISPR 筛选。通过研究发现的数十个因素,我们得出了两个重要的结论:
这些发现为本提案提供了基础。首先,我们发现ESCRT依赖的内体
微自噬需要识别内体上泛素化的 STING,这对 STING 至关重要
降解、自噬体密封和信号调节。致病性物质破坏该途径
ESCRT 亚基突变体(在人类疾病中发现)导致稳定状态下的组成型 STING 信号传导。
其次,我们发现了内质网定位的 STING 与内体蛋白 DNAJC13 的一种新的相互作用,从而导致
限制 STING ER 退出和激活。 DNAJC13 丢失或 ER 内体接触位点破坏
显着提高 STING 活性。定义了 STING 泛素化控制自噬的模型
分辨率,以及 DNAJC13 限制 STING ER 退出,我们建议通过以下方式进一步了解该途径
研究这些过程的潜在机制,包括识别修饰 E3 泛素连接酶
STING 并诱导 ESCRT 依赖性自噬,并确定 STING 诱导的内体的影响
微自噬对病毒感染的影响。我们还将确定 DNAJC13 如何通过改变来阻止 STING 活性
STING 贩运。我们将测试 DNAJC13 和 ER 内体接触在限制 STING 激活中的作用
通过限制 STING ER 退出 TGN。为了定义 STING 相互作用的生化机制,我们将
使用深度突变扫描来寻找 STING 上负责与 DNAJC13 相互作用的基序
了解 DNAJC13 对 STING 运输的影响,以及控制 STING 定位其他方面的基序
和信号。最后,我们将研究涉及人类病理的基因突变如何调节 STING
贩运,影响中枢神经系统细胞的炎症和死亡。更好地理解
STING 运输、降解和信号传导将帮助我们开发抑制 STING 的治疗方法
自身免疫或增强病原体和肿瘤免疫力。
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 }}
Nir Hacohen其他文献
Nir Hacohen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('Nir Hacohen', 18)}}的其他基金
Development of methods for highly multiplexed quantification of cancer proteomes using large-scale nanobody libraries
使用大规模纳米抗体库开发癌症蛋白质组高度多重定量的方法
- 批准号:
10714023 - 财政年份:2023
- 资助金额:
$ 42.36万 - 项目类别:
Factors regulating strength and duration of STING signaling
调节 STING 信号强度和持续时间的因素
- 批准号:
10677771 - 财政年份:2021
- 资助金额:
$ 42.36万 - 项目类别:
Factors regulating strength and duration of STING signaling
调节 STING 信号强度和持续时间的因素
- 批准号:
10367563 - 财政年份:2021
- 资助金额:
$ 42.36万 - 项目类别:
Regulation, function and localization of monocytes in autoimmune tissues
自身免疫组织中单核细胞的调节、功能和定位
- 批准号:
10598099 - 财政年份:2021
- 资助金额:
$ 42.36万 - 项目类别:
Regulation, function and localization of monocytes in autoimmune tissues
自身免疫组织中单核细胞的调节、功能和定位
- 批准号:
10088789 - 财政年份:2021
- 资助金额:
$ 42.36万 - 项目类别:
Regulation, function and localization of monocytes in autoimmune tissues
自身免疫组织中单核细胞的调节、功能和定位
- 批准号:
10427146 - 财政年份:2021
- 资助金额:
$ 42.36万 - 项目类别:
PREcision Medicine through IntErrogation of Rna in the kidnEy (PREMIERE)
通过肾脏 RNA 检测实现精准医学 (PREMIERE)
- 批准号:
10242728 - 财政年份:2017
- 资助金额:
$ 42.36万 - 项目类别:
PREcision Medicine through IntErrogation of Rna in the kidnEy (PREMIERE)
通过肾脏 RNA 检测实现精准医学 (PREMIERE)
- 批准号:
9910974 - 财政年份:2017
- 资助金额:
$ 42.36万 - 项目类别:
Project 2: Genes required for dendritic cell responses to pathogens and T cells
项目2:树突状细胞对病原体和T细胞做出反应所需的基因
- 批准号:
10207350 - 财政年份:2017
- 资助金额:
$ 42.36万 - 项目类别:
PREcision Medicine through IntErrogation of Rna in the kidnEy (PREMIERE)
通过肾脏 RNA 检测实现精准医学 (PREMIERE)
- 批准号:
10703510 - 财政年份:2017
- 资助金额:
$ 42.36万 - 项目类别:
相似海外基金
Linkage of HIV amino acid variants to protective host alleles at CHD1L and HLA class I loci in an African population
非洲人群中 HIV 氨基酸变异与 CHD1L 和 HLA I 类基因座的保护性宿主等位基因的关联
- 批准号:
502556 - 财政年份:2024
- 资助金额:
$ 42.36万 - 项目类别:
Olfactory Epithelium Responses to Human APOE Alleles
嗅觉上皮对人类 APOE 等位基因的反应
- 批准号:
10659303 - 财政年份:2023
- 资助金额:
$ 42.36万 - 项目类别:
Deeply analyzing MHC class I-restricted peptide presentation mechanistics across alleles, pathways, and disease coupled with TCR discovery/characterization
深入分析跨等位基因、通路和疾病的 MHC I 类限制性肽呈递机制以及 TCR 发现/表征
- 批准号:
10674405 - 财政年份:2023
- 资助金额:
$ 42.36万 - 项目类别:
An off-the-shelf tumor cell vaccine with HLA-matching alleles for the personalized treatment of advanced solid tumors
具有 HLA 匹配等位基因的现成肿瘤细胞疫苗,用于晚期实体瘤的个性化治疗
- 批准号:
10758772 - 财政年份:2023
- 资助金额:
$ 42.36万 - 项目类别:
Identifying genetic variants that modify the effect size of ApoE alleles on late-onset Alzheimer's disease risk
识别改变 ApoE 等位基因对迟发性阿尔茨海默病风险影响大小的遗传变异
- 批准号:
10676499 - 财政年份:2023
- 资助金额:
$ 42.36万 - 项目类别:
New statistical approaches to mapping the functional impact of HLA alleles in multimodal complex disease datasets
绘制多模式复杂疾病数据集中 HLA 等位基因功能影响的新统计方法
- 批准号:
2748611 - 财政年份:2022
- 资助金额:
$ 42.36万 - 项目类别:
Studentship
Genome and epigenome editing of induced pluripotent stem cells for investigating osteoarthritis risk alleles
诱导多能干细胞的基因组和表观基因组编辑用于研究骨关节炎风险等位基因
- 批准号:
10532032 - 财政年份:2022
- 资助金额:
$ 42.36万 - 项目类别:
Recessive lethal alleles linked to seed abortion and their effect on fruit development in blueberries
与种子败育相关的隐性致死等位基因及其对蓝莓果实发育的影响
- 批准号:
22K05630 - 财政年份:2022
- 资助金额:
$ 42.36万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Investigating the Effect of APOE Alleles on Neuro-Immunity of Human Brain Borders in Normal Aging and Alzheimer's Disease Using Single-Cell Multi-Omics and In Vitro Organoids
使用单细胞多组学和体外类器官研究 APOE 等位基因对正常衰老和阿尔茨海默病中人脑边界神经免疫的影响
- 批准号:
10525070 - 财政年份:2022
- 资助金额:
$ 42.36万 - 项目类别:
Leveraging the Evolutionary History to Improve Identification of Trait-Associated Alleles and Risk Stratification Models in Native Hawaiians
利用进化历史来改进夏威夷原住民性状相关等位基因的识别和风险分层模型
- 批准号:
10689017 - 财政年份:2022
- 资助金额:
$ 42.36万 - 项目类别: