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Role of cGAS-STING pathway in aging and sexual dimorphism in diabetic kindey disease

ABSTRACT: We investigated the cGAS-STING inflammatory pathway differential activity among both sexes in T2DN rats and its impact on the temporal progression of the diabetic kidney disease. Here we used both male and female old and young T2DN rats. The cGAS-STING pathway presented distinct protein expression profiles between male and female T2DN rats, which significantly intensify with aging. In male T2DN rats, pro-inflammatory genes are particularly heightened in comparison to female rats of similar age, and such levels are further exacerbated with age. Interestingly, a comprehensive RNA-Seq analysis conducted in the kidney cortex of both sexes of T2DN rats, in younger and older ages, disclosed several central molecules, with crucial genes identified within the cGAS-STING pathway. Our study showed the intricate sexual differences in the development and progression of DKD and proposed the fundamental role of cGAS-STING pathway in disease development.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE243138 | GEO | 2023/09/13

REPOSITORIES: GEO

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Homo sapiens

Project description:Manganese (II) Activates cGAS-STING pathway

| PRJNA309759 | ENA

METTL3-Mediated N6-methyladenosine mRNA Modification and cGAS-STING Pathway Activity in Kidney Fibrosis

Project description:Background Chemical modifications on RNA profoundly impact RNA function and regulation. m6A, the most abundant RNA modification in eukaryotes, plays a pivotal role in diverse cellular processes and disease mechanisms. However, its importance is understudied in human chronic kidney disease (CKD) samples regarding its influence on pathological mechanisms. Methods LC-MS/MS and Methylated RNA Immunoprecipitation (MeRIP) sequencing were utilized to examine alterations in m6A levels and patterns in CKD samples. Overexpression of the m6A writer METTL3 in cultured kidney tubular cells was performed to confirm the impact of m6A in tubular cells and explore the biological functions of m6A modification on target genes. Additionally, tubule-specific deletion of Mettl3 (Ksp-Cre Mettl3f/f) mice and the use of anti-sense oligonucleotides inhibiting Mettl3 expression were utilized to reduce m6A modification in an animal kidney disease model. Results By examining 127 human CKD samples, we observed a significant increase in m6A modification and METTL3 expression in diseased kidneys. Epitranscriptomic analysis unveiled an enrichment of m6A modifications in transcripts associated with the activation of inflammatory signaling pathways, particularly the cGAS-STING pathway. m6A hypermethylation increased mRNA stability in cGAS and STING1, as well as elevated the expression of key proteins within the cGAS-STING pathway. Both the tubule-specific deletion of Mettl3 and the use of anti-sense oligonucleotides to inhibit Mettl3 expression protected mice from inflammation, reduced cytokine expression, decreased immune cell recruitment, and attenuated kidney fibrosis. Conclusions Our research revealed heightened METTL3-mediated m6A modification in fibrotic kidneys, particularly enriching the cGAS-STING pathway. This hypermethylation increased mRNA stability for cGAS and STING1, leading to sterile inflammation and fibrosis.

2024-07-03 | GSE271143 | GEO

cGAS Senses Translation Stress Through Direct Binding to Ribosomes

Project description:The cGAS-STING pathway, a central component of the innate immune system, senses cytosolic DNA and induces interferon-stimulated genes (ISGs) to mediate inflammation. Here we report the unexpected discovery that cGAS senses dysfunctional protein production. Purified ribosomes interact with and stimulate the catalytic activity of recombinant cGAS in vitro. Disruption of the ribosome-associated protein quality control pathway, which detects and resolves ribosome collisions, results in cGAS- and STING-dependent ISG expression, and causes the re-localization of cGAS from the nucleus to the cytosol. Indeed, cGAS preferentially binds collided ribosomes in vitro, and other orthogonal perturbations that lead to elevated levels of collided ribosomes cause re-localization of cGAS as well. Thus, the cGAS-STING pathway senses and responds to translation stress. These findings have implications for the inflammatory responses to viral infection and tumorigenesis, both of which substantially reprogram cellular protein synthesis.

2021-09-09 | PXD019359 | Pride

Transcriptome changes after the transfection of cGAS specific agonist G3-YSD

Project description:The cGAS-STING signalling has been well recognized as the major pathway response to self and non-self DNA molecule in cytoplasm. Here, we measured the temporal transcriptome dynamic changes after cGAS-STING signalling activation based on cGAS specific agonist G3-YSD transfection

2022-12-09 | GSE207458 | GEO

cGAS Senses Translation Stress Through Direct Binding to Ribosomes

Project description:The cGAS-STING pathway, a central component of the innate immune system, senses cytosolic DNA and induces interferon-stimulated genes (ISGs) to mediate inflammation. Here we report the unexpected discovery that cGAS senses dysfunctional translation. Purified ribosomes interact with and stimulate recombinant cGAS catalytic activity in vitro. Disruption of the ribosome-associated protein quality control pathway, which detects and resolves ribosome collisions, results in cGAS- and STING-dependent ISG expression, and cause the re-localization of cGAS from the nucleus to the cytosol. Other orthogonal perturbations that lead to elevated levels of collided ribosomes cause re-localization of cGAS as well. Thus, the cGAS-STING pathway senses and responds to translation stress. These findings have implications for the inflammatory responses to viral infection and tumorigenesis, both of which substantially reprogram cellular protein synthesis.

2020-05-26 | GSE151127 | GEO

Microarray analysis of peripheral blood mononuclear cells isolated from patients with ANCA-associated vasculitis and healthy controls

Project description:Patients with anti-MPO vasculitis have increased serum levels of the signalling molecule cGAMP suggestive of ongoing DNA recognition by the cGAS/STING pathway. Consistent with this gene set enrichment analysis of peripheral blood mononuclear cell transcriptomes from patients with active anti-MPO vasculitis revealed up-regulation of type 1 interferon response genes compared to healthy controls.

2022-08-19 | E-MTAB-12008 | biostudies-arrayexpress

CT26 sorted in vivo tumor cells with Trex1 KO

Project description:The DNA exonuclease TREX1 degrades endogenous cytosolic DNA. Cytosolic DNA triggers the cGAS/STING pathway which increases type I interferon. To investigate the physiological significance of TREX1 loss on in vivo tumor growth, we implanted control and TREX1-deficient CT26 tumor cells into immunocompetent BALB/c hosts.Tumor cells were collected 7 days after tumors reached around 200mm3.

2024-03-12 | E-MTAB-13816 | biostudies-arrayexpress

Gene expression profiles in BMDM cells of Trex1-KO and wild-type mice after treatment of STING antagonists

Project description:Mounting evidence demonstrates that cGAS-STING signaling is the major pathway in sensing cytosolic DNAs. However, aberrant accumulation of self DNA molecules in Trex1 (a 3'-to-5' DNA exonuclease) deficient cells usually causes over-activation of cGAS-STING signaling, which is associated with the pathology of several autoimmune diseases. Here, we investigated gene expression changes in BMDM cells of Trex1 knockout mice after manipulating cGAS-STING signaling activity via treatment of two STING antagonists (SN-011 and H151) .

2021-05-26 | GSE143830 | GEO

Neddylation modification on cGAS of human and mouse

Project description:The cytosolic DNA sensor cyclic GMP-AMP (cGAMP) synthetase (cGAS) has emerged as a fundamental component fueling the anti-pathogen immunity. Because of its pivotal role in initiating innate immune response, the activity of cGAS must be tightly fine-tuned to maintain immune homeostasis in antiviral response. Here, we reported that neddylation modification was indispensable for appropriate cGAS-STING signaling activation. Blocking neddylation pathway using neddylation inhibitor MLN4924 substantially impaired the induction of type I interferon and proinflammatory cytokines, which was selectively dependent on Nedd8 E2 enzyme Ube2m. We further found that deficiency of the Nedd8 E3 ligase Rnf111 greatly attenuated DNA-triggered cGAS activation while not affecting cGAMP induced activation of STING, demonstrating that Rnf111 was the Nedd8 E3 ligase of cGAS. We further identified Lys231 and Lys421 as the key neddylation sites in human cGAS. Mechanistically, Rnf111 interacted with and polyneddylated cGAS, which in turn promoted its dimerization and enhanced the DNA-binding ability, leading to proper cGAS-STING pathway activation. In the same line, the Ube2m or Rnf111 deficiency mice exhibited severe defects in innate immune response and were susceptible to HSV-1 infection. Collectively, our study uncovered a vital role of the Ube2m-Rnf111 neddylation axis in promoting the activity of the cGAS-STING pathway and highlighted the importance of neddylation modification in antiviral defense.

2021-02-22 | PXD024088 | Pride

Interferon Signaling After TBI in Aged Mice

Project description:Type I Interferons (IFN-I) contribute to the neuropathology of traumatic brain injury (TBI) and age-related neurodegenerative disease, where Cyclic GMP-AMP Synthase (cGAS) and the Stimulator of Interferon Genes (STING) pathway are implicated as key inducers of IFN-I responses. This study evaluated cGAS/STING activation, IFN-I signaling and neuroinflammation in the cortex and hippocampus of young and aged C57Bl/6 male mice, 24 hrs after controlled cortical impact injury. TBI increased expression of transcripts related to IFN-I signaling and activation of cGAS in the injured cortex of aged mice compared to younger mice. These observations were confirmed by RT-PCR, western blotting and phosphorylation/activation of STAT1, a downstream IFN-I effector molecule

2021-08-20 | GSE180811 | GEO

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