TFAM deficiency in dendritic cells leads to mitochondrial dysfunction and enhanced antitumor immunity through cGAS-STING pathway
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA928780 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23256500_1.fastq.gz | Fastqsanger.gz | |||
| SRR23256500_2.fastq.gz | Fastqsanger.gz | |||
| SRR23256501_1.fastq.gz | Fastqsanger.gz | |||
| SRR23256501_2.fastq.gz | Fastqsanger.gz | |||
| SRR23256502_1.fastq.gz | Fastqsanger.gz |
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Project description:To investigate the role of TFAM knockout in the regulation of dendritic cell function, we cultured bone marrow-derived dendritic cells from wild type or Tfamflox/flox Cre-lyz2 mice, which were stimulated by tumor supernatant from LLC and harvested for RNA-seq analysis.
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Project description:NRAS is commonly mutated in several different types of human cancer. NRAS-mutant tumors are aggressive and associated with poor outcomes. Although the development of targeted therapies as well as immune checkpoint inhibitors has led to a substantial improvement in the overall survival of patients with NRAS wild-type tumors, current therapies for NRAS-mutant cancers are limited. Here, analysis of RNA-sequencing data revealed a downregulation of the type I interferon response in NRAS-mutant tumors compared with NRAS wild-type tumors, which was associated with poor prognosis in NRAS-mutant melanoma. Knockdown of mutant NRAS, but not wild-type NRAS, enhanced the activation of cGAS-STING signaling. The formation of a trimeric complex between TBK1, STING, and IRF3, which is required for the activation and nuclear translocation, was blocked in NRAS-mutant tumor cells. Inactivation of innate immune signaling by mutant NRAS altered cytokine production, resulting in cell autonomous and non-cell autonomous signaling to prevent tumor cell death and in evasion of tumor immune surveillance. Screening of drugs for the ability to stimulate the release of CXCL10 revealed that SOS1 inhibitors reactivated cGAS-STING signaling in NRAS-mutant tumor cells. Importantly, combining SOS1 inhibitors with STING agonists maximized the activation of cGAS-STING signaling and elicited an increased antitumor immune response in vitro and in vivo. Overall, this study provides insights into the regulation of anti-tumor immunity by mutant NRAS and uncovers a potential strategy for treating NRAS-mutant cancer.
2025-05-11 | GSE290171 | GEO
Project description:While mitochondrial dysfunction is implicated in metabolic dysfunction associated steatohepatitis (MASH), the precise underlying mechanisms remain obscure. Here, we identify the SIRT3-DsbA-L-TFAM axis as a crucial suppressor for mitochondrial stress-induced cGAS activation in the hepatocytes, thereby alleviating MASH in mice. SIRT3 facilitates the deacetylation of Disulfide-bond-A oxidoreductase-like protein (DsbA-L) at lysine residues (Lys165, Lys167, and Lys177), which promotes the interaction between DsbA-L and mitochondrial transcription factor A (TFAM), essential for the preservation of mitochondrial integrity and function. Hepatocyte-specific knockout of SIRT3 or DsbA-L in male mice promoted mitochondrial DNA release into the cytosol, resulting in activation of the cGAS-STING pathway and exacerbation of MASH characteristics. Conversely, hepatocyte-specific knockout of cGAS or overexpression of DsbA-L mitigated diet- and SIRT3 deficiency-induced MASH progression. Our study underscores the clinical significance of targeting SIRT3 and cGAS as pivotal therapeutic avenues to inhibit the progression of MASH.
2024-11-30 | GSE281667 | GEO
Project description:Immune checkpoint blockade (ICB) has obtained significant progress in treating multiple types of cancers, but its overall response rate and therapeutic efficacies are not yet satisfactory. To fulfil such needs, identification of combinational approach to enhance the therapeutic efficacies of ICB is highly demanded. The activation of cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling is critical to elicit the antitumor innate immune responses and a promising target to develop combinational immunotherapy. Accordingly, the application of STING agonist exhibits potent antitumor functions in preclinical models and is currently tested in clinical trials. However, deregulation of cGAS-STING is frequently observed in cancers and substantially attenuates the efficacies of treatments by harnessing cGAS-STING signaling. Hence, the underlying mechanisms of maintaining intracellular homeostasis of cGAS-STING need to be elucidated. Here we report the identification of PIKfyve as a negative regulator of cGAS-STING signaling. Inhibition of PIKfyve by kinase inhibitor YM201636 or genetic ablation markedly provokes the expression of cGAS-STING downstream IFN-stimulated genes (ISGs) and reschedules the antitumor microenvironment by recruiting CD8+ T lymphocytes. In melanoma models, PIKfyve inhibition confers sensitivity to the combinational therapy of cisplatin and anti-PD1, leading to a durable treatment response. Mechanistically, PIKfyve interacts with STING to promote its lysosomal degradation. These results highlight the importance of maintaining STING homeostasis as a direction to augment the efficacies of combinational immunotherapies
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Project description:MATRIN3 deficiency leads to cGAS-STING activation
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Project description:MATRIN3 deficiency leads to cGAS-STING activation
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Project description:The goal of this analysis was to utilize microarray profiling to identify basal alterations in gene expression in response to TFAM depletion and mtDNA stress. Mitochondrial DNA (mtDNA) is normally present at thousands of copies per cell and is packaged into several hundred higher-order structures termed nucleoids. The abundant mtDNA-binding protein, TFAM (transcription factor A,mitochondrial), regulates nucleoid architecture, abundance and segregation. Complete mtDNA depletion profoundly impairs oxidative phosphorylation, triggering calcium-dependent stress signalling and adaptive metabolic responses. However, the cellular responses to mtDNA instability, a physiologically relevant stress observed in many human diseases and ageing, remain poorly defined. Here we show that moderate mtDNA stress elicited by TFAM deficiency engages cytosolic antiviral signalling to enhance the expression of a subset of interferon-stimulated genes. Mechanistically, we find that aberrant mtDNA packaging promotes escape of mtDNA into the cytosol, where it engages the DNA sensor cGAS (also known as MB21D1) and promotes STING (also known as TMEM173)–IRF3-dependent signalling to elevate interferon-stimulated gene expression, potentiate type I interferon responses and confer broad viral resistance. Furthermore, we demonstrate that herpesviruses induce mtDNA stress, which enhances antiviral signalling and type I interferon responses during infection. Our results further demonstrate that mitochondria are central participants in innate immunity, identify mtDNA stress as a cell-intrinsic trigger of antiviral signaling and suggest that cellular monitoring of mtDNA homeostasis cooperates with canonical virus sensing mechanisms to fully engage antiviral innate immunity. Murine embryonic fibroblasts were isolated from wild-type or Tfam+/- E13.5 littermate embryos. RNA from passage-matched wild-type and Tfam+/- MEF lines was extracted in duplicate and hybridized onto Affymetrix microarrays. Four arrays were performed in total with two technical replicates per genotype.
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Project description:MATRIN3 deficiency leads to cGAS-STING activation (NanoString)
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Project description:53BP1 loss elicits cGAS-STING-dependent antitumor immunity in ovarian and pancreatic cancer
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Project description:Low-grade inflammation is a hallmark of old age and a central driver of ageing-associated impairment and disease. Multiple factors can contribute to ageing-associated inflammation, however the molecular pathways transducing aberrant inflammatory signalling and their impact in natural ageing remain poorly understood. Here we show that the cGAS-STING signalling pathway, mediating immune sensing of DNA, is a critical driver of chronic inflammation and functional decline during ageing. Blockade of STING suppresses the inflammatory phenotypes of senescent human cells and tissues, attenuates ageing-related inflammation in multiple peripheral organs and the brain in mice, and leads to an improvement in tissue function. Focusing on the ageing brain, we reveal that activation of STING triggers reactive microglia transcriptional states, neurodegeneration and cognitive decline. Cytosolic DNA released from perturbed mitochondria elicits cGAS activity in old microglia defining a mechanism by which cGAS-STING signalling is engaged in the ageing brain. Single-nuclei RNA-sequencing (snRNA-seq) of microglia and hippocampi of a newly developed cGAS gain-of-function mouse model demonstrates that engagement of cGAS in microglia is sufficient to direct ageing-associated transcriptional microglia states leading to bystander cell inflammation, neurotoxicity and impaired memory capacity. Our findings establish the cGAS-STING pathway as a critical driver of ageing-related inflammation in peripheral organs and the brain, and reveal blockade of cGAS-STING signalling as a potential strategy to halt (neuro)degenerative processes during old age.
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