Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1007232 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25728072.fastq.gz | Fastqsanger.gz | |||
| SRR25728073.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 2 of 2 |
Similar Datasets
Project description:SIRT5 is one of the seven members of the NAD+-dependent sirtuin family of protein deacylase that is mainly present in mitochondria and regulates metabolism. In heart, SIRT5 is highly expressed and responsible for succinylation on metabolic enzymes. Although the role of SIRT5 in maintaining cardiac homeostasis under physiological stress and few potential substrates of SIRT5 have been preliminarily revealed, the regulatory network and key cellular signaling pathways involving SIRT5 in myocardial hypertrophy remain largely unknown. Here, we used an established murine model of pressure overload-induced myocardial hypertrophy caused by transverse aortic constriction (TAC) to outline the network and pathway involving SIRT5 in cardiac stress responses. Remarkably, SIRT5 KO mice had enhanced myocardial hypertrophy after TAC surgery compared with wild-type mice.
2024-10-05 | GSE186985 | GEO
Project description:<p>SIRT5 deficiency caused widespread protein hypersuccinylation in cardiac tissue. Succinylation proteomic analysis revealed HADHB as the key SIRT5 target, with lysine 292 (K292) being the dominant succinylation site. Functional studies demonstrated that K292 succinylation impairs HADHB-mediated fatty acid β-oxidation, ultimately promoting cardiomyocyte senescence. These findings reveal a critical regulatory axis involving SIRT5-HADHB succinylation in the pathogenesis of radiation-induced cardiomyopathy, providing new insights into potential therapeutic strategies.</p>
2026-03-15 | MTBLS14057 | MetaboLights
Project description:Objectives: To explore how modulation of cardiomyocyte SIRT5 levels affects the development of pathological cardiac remodeling and dysfunction. Background: SIRT5 is a mitochondrial NAD+-dependent deacylase, which regulates metabolic enzymes upon desuccinylation, demalonylation, and deglutarylation. Its role in the development of heart failure is not completely understood. Methods: Mice with cardiomyocyte-specific Sirt5 deletion (Sirt5-/-) or Sirt5 overexpression (cSirt5-Tg) underwent transverse aortic constriction (TAC) or Sham surgery. Cardiac structure and function were assessed by echocardiography and quantification of myocardial fibrosis and cardiomyocyte cell size. Metabolomic analysis and RNA sequencing were performed to identify potential novel pathways regulated by SIRT5. Results: While cardiac structure and function were similar in cSirt5-Tg compared to control mice, cSirt5-/- mice displayed exacerbated cardiac dilation, dysfunction, and fibrosis following TAC. Accumulation of metabolites involved in purine metabolism, particularly inosine and hypoxanthine, and reductions in nucleosides, adenosine and adenine, and nucleotides, AMP and ADP, were observed in hearts of cSirt5-/- mice and following TAC. Moreover, transcriptional analysis revealed upregulation of purine-nucleoside phosphorylase (PNP) and 5' nucleotidase, ecto (NT5E) and downregulation of adenosine kinase (ADK), which is likely to contribute to enhanced degradation of purine nucleotides and resulting accumulation of inosine and hypoxanthine in hearts of cSirt5-/- mice following TAC. Lastly, reduced SIRT5 expression and protein succinylation in left-ventricular tissue of patients with heart failure correlates with reduced ADK expression. Conclusions: Loss of SIRT5 aggravates cardiac remodeling and dysfunction in response to chronic pressure-overload possibly by dysregulation of genes involved in purine and pyrimidine metabolism, resulting in impaired ATP regeneration from adenosine.
2025-12-02 | GSE280863 | GEO
Project description:The cytokines tumor necrosis factor ligand superfamily member 11 (TNFSF11; also known as RANKL) and macrophage colony-stimulating factor 1 receptor (M-CSF) differentiate macrophages into bone-resorbing osteoclasts via a process characterised by changes in metabolic activity that support energy-consuming processes such as cell fusion or bone resorption. Treatment with RANKL triggers a phenotype of accelerated metabolism with enhanced glycolysis and an initial disruption of the tricarboxylic acid cycle (TCA) cycle through increased expression of the enzyme aconitate decarboxylase (ACOD1). which results in an upregulation of intracellular succinate levels. Succinate then causes post-translational succinylation of lysine residues. Interestingly, ACOD1 as an inducer of protein succinylation and the desuccinylase NAD-dependent protein deacylase sirtuin-5, mitochondrial (SIRT5) are regulated differentially and the initially high expression of ACOD1 decreases towards the end of differentiation, whereas SIRT5 levels increase. To mimic the effect of protein succinylation, diethyl succinate or a SIRT5 inhibitor were added to differentiating osteoclasts, which reduced the formation of large osteoclasts, showing its relevance for successful osteoclastogenesis. To identify proteins succinylated after RANKL treatment, we used an immunoaffinity-based liquid chromatography–tandem mass spectrometry (LC-MS/MS) approach. Most lysine succinylated proteins were metabolic enzymes localised in the mitochondria. Citrate synthase, the enzyme catalysing the first reaction of the TCA cycle, showed a notable difference in succinylation levels before and after RANKL stimulation, with succinylation detected exclusively in stimulated cells. Immunoprecipitation assays confirmed citrate synthase succinylation. Using whole cell extracts, we observed that RANKL treatment decreased CS activity in a concentration-dependent manner. This suggests that CS could be a critical factor in the context of energy production during osteoclastogenesis and that protein succinylation helps to modulate the differentiation program of osteoclasts.
2025-07-21 | PXD060675 | Pride
Project description:Osteoarthritis (OA) is characterized by progressive cartilage degradation and chondrocyte apoptosis, yet the regulatory mechanisms remain incompletely understood. Here, we identified lysine succinylation and its dynamic modulation by the desuccinylase sirtuin 5 (SIRT5) and the succinyltransferase carnitine palmitoyltransferase 1A (CPT1A) as critical regulators of OA progression. Inflammatory stimulation suppressed global succinylation levels in chondrocytes, accompanied by decreased CPT1A and increased SIRT5 expression. In vitro, CPT1A knockdown exacerbated extracellular matrix (ECM) degradation and apoptosis, whereas silencing SIRT5 restored succinylation and protected cartilage matrix integrity. Consistently, in vivo intra-articular knockdown of CPT1A promoted OA progression, while SIRT5 knockdown alleviated cartilage damage. Proteomic analysis identified polyadenylate-binding protein 1 (PABP1) as a key succinylated effector, with succinylation at lysine 208 essential for attenuating ECM catabolism and apoptosis. Mechanistically, succinylated PABP1 competitively bound IKKβ, displacing TGF-β activated kinase 1 (TAK1) and inhibiting NFκB signaling activation. Furthermore, we identified tiotropium via high-throughput screening as a pharmacological agent that enhances PABP1 succinylation, thereby suppressing ECM degradation and chondrocyte apoptosis both in vitro and in vivo. Population-based data from the UK Biobank indicated that tiotropium use was associated with a significantly lower risk of OA development and joint replacement. Collectively, our findings reveal a novel SIRT5/CPT1A-PABP1 succinylation axis that controls OA pathogenesis via NFκB signaling, highlighting tiotropium as a promising therapeutic candidate for OA intervention.
| PXD065832 |
Project description:Hepatocellular carcinoma (HCC) is a prototypical inflammation-associated cancer and the tumor microenvironment (TME) plays a pivotal role in HCC pathogenesis and response to therapy. The liver is a metabolically active organ, but how liver metabolism impacts TME during HCC development and response to immunotherapy are poorly understood. Here, we show that the metabolic regulator SIRT5 is downregulated in human primary HCC samples, and that Sirt5 deficiency in mice synergizes with oncogenes to increase bile acid (BA) production, which is due to hypersuccinylation and increased BA biosynthesis in the peroxisome. BA acts as a cell-signaling mediator to stimulate its nuclear receptor and promotes M2-like macrophage polarization, thereby creating an immunosuppressive microenvironment favorable for HCC initiating cells. Furthermore, high serum taurocholic acid, a major primary BA, correlates with low SIRT5 expression and increased M2-like tumor-associated macrophages (TAMs) in liver tissue samples from HCC patients. Importantly, administration of cholestyramine, a BA sequestrant and FDA-approved medication for hyperlipemia, reverses the effect of Sirt5 deficiency on promoting M2-like polarized TAMs and liver tumor growth. Our study thus uncovers a novel function of SIRT5 in orchestrating BA metabolism to prevent tumor immune evasion and suppress HCC. These results also suggest a potential strategy using clinically proven bile acid sequestrants for the treatment of HCC patients, especially those with decreased SIRT5 and abnormally high BAs.
2022-01-10 | GSE193213 | GEO
Project description:Posttranslational modification succinylation plays a pivotal role in tumorigenesis across malignancies, yet its mechanistic contributions to hepatocellular carcinoma (HCC) pathogenesis and therapeutic resistance remain poorly characterized. In this study, we systematically demonstrated that the splicing factor SRSF11 undergoes functional consequential succinylation in HCC progression. Mechanistically, lysine acetyltransferase 2A (KAT2A) directly interacts with SRSF11 to catalyze its succinylation at lysine 419 (K419), thereby enhancing DNA damage repair capacity in both in vitro and in vivo HCC models. Structural and functional analyses revealed that K419 succinylation stabilizes SRSF11-spliceosome interactions, which promote the inclusion of exon 10 of RAD52 through enhanced pre-mRNAs binding. This exon-specific splicing event preserves the RAD51-binding domain essential for homologous recombination (HR) repair, ultimately facilitating RAD52-RAD51 dimer assembly and HR-mediated genomic stabilization. Clinically, elevated SRSF11 expression is correlated with increased HR activity, radioresistance, and reduced survival in HCC patients. Notably, genetic disruption of the KAT2A-SRSF11 axis sensitizes HCC cells to radiation-induced apoptosis. Our findings establish succinylation as a novel regulatory mechanism linking alternative splicing to DNA repair fidelity in HCC, while proposing therapeutic targeting of this pathway to overcome radioresistance in advanced HCC.
2025-12-04 | GSE304385 | GEO
Project description:Posttranslational modification succinylation plays a pivotal role in tumorigenesis across malignancies, yet its mechanistic contributions to hepatocellular carcinoma (HCC) pathogenesis and therapeutic resistance remain poorly characterized. In this study, we systematically demonstrated that the splicing factor SRSF11 undergoes functional consequential succinylation in HCC progression. Mechanistically, lysine acetyltransferase 2A (KAT2A) directly interacts with SRSF11 to catalyze its succinylation at lysine 419 (K419), thereby enhancing DNA damage repair capacity in both in vitro and in vivo HCC models. Structural and functional analyses revealed that K419 succinylation stabilizes SRSF11-spliceosome interactions, which promote the inclusion of exon 10 of RAD52 through enhanced pre-mRNAs binding. This exon-specific splicing event preserves the RAD51-binding domain essential for homologous recombination (HR) repair, ultimately facilitating RAD52-RAD51 dimer assembly and HR-mediated genomic stabilization. Clinically, elevated SRSF11 expression is correlated with increased HR activity, radioresistance, and reduced survival in HCC patients. Notably, genetic disruption of the KAT2A-SRSF11 axis sensitizes HCC cells to radiation-induced apoptosis. Our findings establish succinylation as a novel regulatory mechanism linking alternative splicing to DNA repair fidelity in HCC, while proposing therapeutic targeting of this pathway to overcome radioresistance in advanced HCC.
2025-12-04 | GSE304384 | GEO
Project description:Mitochondrial Sirtuin 5 (SIRT5) is an NAD+-dependent demalonylase, desuccinylase, and deglutarylase that controls several metabolic pathways. A number of recent studies point to SIRT5 desuccinylase activity being important in maintaining cardiac function and metabolism under stress. Previously, we described a phenotype of increased mortality in whole-body SIRT5KO mice exposed to chronic pressure overload compared to their littermate WT controls. We developed a tamoxifen-inducible, heart-specific SIRT5KO mouse model to determine if the survival phenotype we reported was due to a cardiac-intrinsic or cardiac-extrinsic effect of SIRT5. We discovered that postnatal cardiac ablation of Sirt5 resulted in persistent accumulation of protein succinylation up to 30 weeks after SIRT5 depletion. Succinyl proteomics revealed that succinylation increased on proteins of oxidative metabolism between 15 and 31 weeks post ablation. Heart-specific SIRT5KO mice were exposed to chronic pressure overload to induce cardiac hypertrophy. We found that, in contrast to whole-body SIRT5KO mice, there was no difference in survival between heart-specific SIRT5KO mice and their littermate controls. Overall, the data presented here suggest that survival in SIRT5KO mice may be dictated by a multi-tissue or prenatal effect of SIRT5.
2018-05-16 | PXD008728 | Pride
Project description:Histone post-translational modifications (PTMs) are key players in chromatin regulation. The recent identification of novel histone acylations raised important questions regarding their role in transcriptional regulation. In this study, we characterized the role of succinylation of H3K122 (H3K122succ), located on the lateral surface of the histone octamer, in transcription and in chromatin function. Using chromatin, site-specifically succinylated at H3K122, we found that the presence of H3K122succ is sufficient to stimulate transcription in vitro. In line with this H3K122succ was enriched on promoters of active genes in mammalian cells and enrichment levels scale with gene expression. Furthermore, we show that the p300 and CBP co-activators are H3K122 succinyltransferases and identify sirtuin 5 (SIRT5) as a new desuccinylase. By applying single molecule FRET assays we demonstrate a direct effect of H3K122succ on nucleosome stability indicating an important role for histone succinylation in modulating chromatin dynamics. Together, these data provide the first insights into the molecular mechanisms of H3K122succ in transcriptional regulation and they highlight a structural function for H3K122succ through direct perturbation of nucleosomes.
2021-02-01 | GSE152019 | GEO