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:10367563
- 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
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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Nir Hacohen其他文献
Nir Hacohen的其他文献
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{{ 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:
10490901 - 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
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10598099 - 财政年份:2021
- 资助金额:
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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
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PREcision Medicine through IntErrogation of Rna in the kidnEy (PREMIERE)
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$ 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:
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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
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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:
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