Activation of cGAS-STING signal to inhibit the proliferation of bladder cancer: the immune effect of cisplatin
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE165767 | GEO | 2021/03/31
REPOSITORIES: GEO
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Project description:Activation of cGAS-STING signal to inhibit the proliferation of bladder cancer: the immune effect of cisplatin
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Project description:Cyclic GMP-AMP synthase (cGAS) binds pathogenic and other cytoplasmic double-stranded DNA (dsDNA) to catalyze the synthesis of cyclic GMP-AMP (cGAMP), which serves as the secondary messenger to activate the STING pathway and innate immune responses. Emerging evidence suggests that activation of the cGAS pathway is crucial for anti-tumor immunity, however, no effective intervention method targeting cGAS is currently available. Here we report that cGAS is palmitoylated by ZDHHC9 at cysteines 404/405, which promotes the dimerization and activation of cGAS. We further identified that lysophospholipase-like 1 (LYPLAL1) depalmitoylates cGAS to compromise its normal function. As such, inhibition of LYPLAL1 significantly enhances cGAS-mediated innate immune response, elevates PD-L1 expression and enhances anti-tumor response to PD-1 blockade. Our results therefore reveal that targeting LYPLAL1-mediated cGAS depalmitoylation contributes to cGAS activation, providing a potential strategy to augment the efficacy of anti-tumor immunotherapy.
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Project description:DNA is strictly compartmentalised within the nucleus to prevent autoimmunity despite this cGAS, a cytosolic sensor of dsDNA, is activated in autoinflammatory disorders and by DNA damage. Precisely how cellular DNA gains access to the cytoplasm remains to be determined. Here, we report that cGAS localises to micronuclei arising from genome instability in a model of monogenic autoinflammation, after exogenous DNA damage and spontaneously in human cancer cells. These micronuclei occur after mis-segregation of DNA during cell division and consist of chromatin surrounded by their own nuclear membrane. Breakdown of the micronuclear envelope, a process associated with chromothripsis, leads to rapid accumulation of cGAS, providing a mechanism by which self-DNA becomes exposed to the cytosol. cGAS binds to and is activated by chromatin and consistent with a mitotic origin, micronuclei formation and the proinflammatory response following DNA-damage are cell-cycle dependent. Furthermore, by combining live-cell laser microdissection with single cell transcriptomics, we establish that induction of interferon stimulated gene expression occurs in micronucleated cells. We therefore conclude that micronuclei represent an important source of immunostimulatory DNA. As micronuclei formed from lagging chromosomes also activate this pathway, cGAS recognition of micronuclei may act as a cell-intrinsic immune surveillance mechanism detecting a range of neoplasia-inducing processes.
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Project description:Bladder cancer characterized by RNA methylation abnormalities and NOTCH pathway dysregulation exhibits high recurrence that remains the major obstacle for bladder cancer treatment. Targeting methyltransferase-like 3 (METTL3) and NOTCH signal is a potential strategy to block bladder cancer progression. However, the underlying mechanisms by which METTL3-manipulated NOTCH signal and its effect on bladder cancer tumorigenesis remain to be clarified. Here we showed that METTL3-guided m6A modification methylated pri-miR-146 at the flaking sequence, which was responsible for the pri-miR-146 maturation. Furthermore, NUMB/NOTCH2 axis was identified as the functional downstream target signal that mediated the pro-survival role of miR-146a-5p in bladder cancer cells. Therapeutically, the polypeptide melittin was demonstrated to induce apoptosis of bladder cancer cells in a METTL3-dependent manner. Importantly, METTL3 and miR-146a-5p were positively correlated with recurrence and poor prognosis of bladder cancer patient. Our studies indicate that METTL3/miR-146a-5p/NUMB/NOTCH2 axis could be a potential therapeutic target for recurrent bladder cancer treatment and METTL3 acts as a fate determinant that controls sensitivity of bladder cancer cells to melittin treatment.
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Project description:Cyclic GMP-AMP synthase (cGAS) is a cytosolic double-strand DNA (dsDNA) sensor in innate immune cells. A function of cGAS is to detect cytosolic double-stranded DNA and synthesize the cyclic dinucleotide 2'3'-cGAMP. This second messenger binds to and activates the adaptor protein STING, triggering the TBK1-IRF3 signaling pathway. However, the function of cGAS in T cells remain unknown and its role in adaptive immunity is also poorly characterized. Here we show that nuclear cGAS promotes regulatory T cell (Treg) development by cooperating with the genome organizer CTCF through a T cell-intrinsic and synthase function-independent way. Conditional deletion of cGAS using Foxp3Cre-YFP Cgasfl/fl and CD4Cre Cgasfl/fl mice demonstrated that cGAS imprints thymocytes for Treg development before the expression of FOXP3. cGAS also promotes the FOXP3 inheritability and suppressive activity of Treg. At steady state, cGAS is located in the nucleus of Treg, while stimulation of naïve CD4+ T cell with anti-CD3/CD28 antibodies induces transcription of cGAS and its translocation into nucleus. ATAC-sequencing of thymic Treg and Treg precursors revealed that CTCF binding is reduced in mature Treg. Mechanistically, cGAS interacts with CTCF and recruits CTCF to Tnfrsf9 (4-1BB) and Tnfrsf4 (OX40) gene locus to maintain their stable transcription through formation of chromatin loops. Physiologically, in mouse tumor model, Treg specific deletion of cGAS reduced tumor growth. Therefore, we uncovered a T cell-intrinsic role of nuclear cGAS in maintaining Treg development and function by imprinting the genome architecture with CTCF.
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Project description:Cyclic GMP-AMP synthase (cGAS) is a cytosolic double-strand DNA (dsDNA) sensor in innate immune cells. A function of cGAS is to detect cytosolic double-stranded DNA and synthesize the cyclic dinucleotide 2'3'-cGAMP. This second messenger binds to and activates the adaptor protein STING, triggering the TBK1-IRF3 signaling pathway. However, the function of cGAS in T cells remain unknown and its role in adaptive immunity is also poorly characterized. Here we show that nuclear cGAS promotes regulatory T cell (Treg) development by cooperating with the genome organizer CTCF through a T cell-intrinsic and synthase function-independent way. Conditional deletion of cGAS using Foxp3Cre-YFP Cgasfl/fl and CD4Cre Cgasfl/fl mice demonstrated that cGAS imprints thymocytes for Treg development before the expression of FOXP3. cGAS also promotes the FOXP3 inheritability and suppressive activity of Treg. At steady state, cGAS is located in the nucleus of Treg, while stimulation of naïve CD4+ T cell with anti-CD3/CD28 antibodies induces transcription of cGAS and its translocation into nucleus. ATAC-sequencing of thymic Treg and Treg precursors revealed that CTCF binding is reduced in mature Treg. Mechanistically, cGAS interacts with CTCF and recruits CTCF to Tnfrsf9 (4-1BB) and Tnfrsf4 (OX40) gene locus to maintain their stable transcription through formation of chromatin loops. Physiologically, in mouse tumor model, Treg specific deletion of cGAS reduced tumor growth. Therefore, we uncovered a T cell-intrinsic role of nuclear cGAS in maintaining Treg development and function by imprinting the genome architecture with CTCF.
2025-08-07 | GSE301663 | GEO
Project description:Cyclic GMP-AMP synthase (cGAS) is a cytosolic double-strand DNA (dsDNA) sensor in innate immune cells. A function of cGAS is to detect cytosolic double-stranded DNA and synthesize the cyclic dinucleotide 2'3'-cGAMP. This second messenger binds to and activates the adaptor protein STING, triggering the TBK1-IRF3 signaling pathway. However, the function of cGAS in T cells remain unknown and its role in adaptive immunity is also poorly characterized. Here we show that nuclear cGAS promotes regulatory T cell (Treg) development by cooperating with the genome organizer CTCF through a T cell-intrinsic and synthase function-independent way. Conditional deletion of cGAS using Foxp3Cre-YFP Cgasfl/fl and CD4Cre Cgasfl/fl mice demonstrated that cGAS imprints thymocytes for Treg development before the expression of FOXP3. cGAS also promotes the FOXP3 inheritability and suppressive activity of Treg. At steady state, cGAS is located in the nucleus of Treg, while stimulation of naïve CD4+ T cell with anti-CD3/CD28 antibodies induces transcription of cGAS and its translocation into nucleus. ATAC-sequencing of thymic Treg and Treg precursors revealed that CTCF binding is reduced in mature Treg. Mechanistically, cGAS interacts with CTCF and recruits CTCF to Tnfrsf9 (4-1BB) and Tnfrsf4 (OX40) gene locus to maintain their stable transcription through formation of chromatin loops. Physiologically, in mouse tumor model, Treg specific deletion of cGAS reduced tumor growth. Therefore, we uncovered a T cell-intrinsic role of nuclear cGAS in maintaining Treg development and function by imprinting the genome architecture with CTCF.
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Project description:Cyclic GMP-AMP synthase (cGAS) is a cytosolic double-strand DNA (dsDNA) sensor in innate immune cells. A function of cGAS is to detect cytosolic double-stranded DNA and synthesize the cyclic dinucleotide 2'3'-cGAMP. This second messenger binds to and activates the adaptor protein STING, triggering the TBK1-IRF3 signaling pathway. However, the function of cGAS in T cells remain unknown and its role in adaptive immunity is also poorly characterized. Here we show that nuclear cGAS promotes regulatory T cell (Treg) development by cooperating with the genome organizer CTCF through a T cell-intrinsic and synthase function-independent way. Conditional deletion of cGAS using Foxp3Cre-YFP Cgasfl/fl and CD4Cre Cgasfl/fl mice demonstrated that cGAS imprints thymocytes for Treg development before the expression of FOXP3. cGAS also promotes the FOXP3 inheritability and suppressive activity of Treg. At steady state, cGAS is located in the nucleus of Treg, while stimulation of naïve CD4+ T cell with anti-CD3/CD28 antibodies induces transcription of cGAS and its translocation into nucleus. ATAC-sequencing of thymic Treg and Treg precursors revealed that CTCF binding is reduced in mature Treg. Mechanistically, cGAS interacts with CTCF and recruits CTCF to Tnfrsf9 (4-1BB) and Tnfrsf4 (OX40) gene locus to maintain their stable transcription through formation of chromatin loops. Physiologically, in mouse tumor model, Treg specific deletion of cGAS reduced tumor growth. Therefore, we uncovered a T cell-intrinsic role of nuclear cGAS in maintaining Treg development and function by imprinting the genome architecture with CTCF.
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