Deacetylation of Sirt2 regulates PKM2 ubiquitination and its effect on liver glucose metabolism
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE229161 | GEO | 2023/04/08
REPOSITORIES: GEO
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Project description:Deacetylation of Sirt2 regulates PKM2 ubiquitination and its effect on liver glucose metabolism
| PRJNA953144 | ENA
Project description:Metabolism is a key driver of T cell functions, and the switch from oxidative-phosphorylation to aerobic glycolysis is a hallmark of T cell activation. However, the mechanisms underlying the metabolic switch remain unclear. Here, we report that the Sirtuin-2 (Sirt2) deacetylase protein functions as a metabolic checkpoint that harnesses T cell effector functions and impairs anti-tumor immunity. Specifically, upregulation of Sirt2 expression in human tumor-infiltrating T lymphocytes (TILs) negatively correlates with response to Nivolumab and TIL therapy in non-small cell lung cancer. Mechanistically, Sirt2 suppresses aerobic glycolysis by deacetylating key glycolytic enzymes. Accordingly, Sirt2-deficient T cells manifest increased glycolysis, display enhanced proliferation and effector functions, and have superior anti-tumor activity. Importantly, pharmacologic inhibition of Sirt2 endows human TILs with these superior metabolic fitness and enhanced effector functions. These findings indicate Sirt2 as an actionable target for reprogramming T cell metabolism to augment a broad spectrum of cancer immunotherapies.
2020-09-16 | GSE151421 | GEO
Project description:Growing evidence indicates that metabolism is a key driver of T cell functions. A switch from oxidative phosphorylation to aerobic glycolysis is a hallmark of T cell activation and is required to meet metabolic demands of proliferation and effector functions. However, the mechanisms underlying the metabolic switch in T cells remain unclear. Here, we identify Sirt2 as a crucial immune checkpoint coordinating metabolic and functional fitness of T cells. Sirt2 is induced upon T cell activation and increases in late maturation stages. Sirt2 negatively regulates glycolysis by targeting key glycolytic enzymes. Remarkably, Sirt2 knockout T cells exhibit profound upregulation of aerobic glycolysis with enhanced proliferation and effector function and thus effectively reject tumor challenge in vivo. Furthermore, pharmacologic inhibition of Sirt2 in human tumor infiltrating lymphocytes demonstrated a similar phenotype. Taken together, our results demonstrate Sirt2 as an actionable target to reprogram T cell metabolism to augment immunotherapy.
2020-06-15 | PXD012811 | Pride
Project description:Growing evidence indicates that metabolism is a key driver of T cell functions. A switch from oxidative phosphorylation to aerobic glycolysis is a hallmark of T cell activation and is required to meet metabolic demands of proliferation and effector functions. However, the mechanisms underlying the metabolic switch in T cells remain unclear. Here, we identify Sirt2 as a crucial immune checkpoint coordinating metabolic and functional fitness of T cells. Sirt2 is induced upon T cell activation and increases in late maturation stages. Sirt2 negatively regulates glycolysis by targeting key glycolytic enzymes. Remarkably, Sirt2 knockout T cells exhibit profound upregulation of aerobic glycolysis with enhanced proliferation and effector function and thus effectively reject tumor challenge in vivo. Furthermore, pharmacologic inhibition of Sirt2 in human tumor infiltrating lymphocytes demonstrated a similar phenotype. Taken together, our results demonstrate Sirt2 as an actionable target to reprogram T cell metabolism to augment immunotherapy.
2020-07-03 | PXD020150 | Pride
Project description:Dysregulated metabolism is a key driver of maladaptive tumor-reactive T lymphocytes within the tumor microenvironment (TME). Actionable mechanisms that rescue the effector activity of anti-tumor T cells in a metabolically restricted TME remain elusive. Here, we report that the Sirtuin-2 (Sirt2) protein deacetylase functions as a master metabolic checkpoint that inhibits T cell metabolic fitness and impairs T cell effector functions and anti-tumor immunity. Mechanistically, Sirt2 suppresses glycolysis and oxidative-phosphorylation (OxPhos) by deacetylating key enzymes involved in glycolysis, tricarboxylic acid (TCA)-cycle, fatty acid oxidation (FAO) and glutaminolysis. Accordingly, Sirt2-deficient T cells exhibit a hyper-metabolic activity with increased glycolysis and OxPhos, resulting in enhanced proliferation and effector functions at tumor beds and subsequently exhibiting superior anti-tumor activity. Importantly, pharmacologic inhibition of Sirt2 endows human lung tumor-infiltrating lymphocytes (TILs) with these superior metabolic fitness and enhanced effector functions. Furthermore, upregulation of Sirt2 expression in human TILs negatively correlates with response to Nivolumab and TIL therapy in non-small cell lung cancer (NSCLC). Our findings unveil Sirt2 as an unexpected actionable target for reprogramming T cell metabolism to augment a broad spectrum of cancer immunotherapies.
2020-06-16 | PXD019763 | Pride
Project description:Growing evidence indicates that metabolism is a key driver of T cell functions. A switch from oxidative phosphorylation to aerobic glycolysis is a hallmark of T cell activation and is required to meet metabolic demands of proliferation and effector functions. However, the mechanisms underlying the metabolic switch in T cells remain unclear. Here, we identify Sirt2 as a crucial immune checkpoint coordinating metabolic and functional fitness of T cells. Sirt2 is induced upon T cell activation and increases in late maturation stages. Sirt2 negatively regulates glycolysis by targeting key glycolytic enzymes. Remarkably, Sirt2 knockout T cells exhibit profound upregulation of aerobic glycolysis with enhanced proliferation and effector function and thus effectively reject tumor challenge in vivo. Furthermore, pharmacologic inhibition of Sirt2 in human tumor infiltrating lymphocytes demonstrated a similar phenotype. Taken together, our results demonstrate Sirt2 as an actionable target to reprogram T cell metabolism to augment immunotherapy.
2020-06-15 | PXD012796 | Pride
Project description:To investigate the differentially expressed RNA levels in the liver of aged LoxP and SIRT2-KOhep mice. We then performed gene expression profiling analysis using data obtained from RNA-seq of liver of aged LoxP and SIRT2-KOhep mice
2023-04-30 | GSE228204 | GEO
Project description:Sirtuin-2 (Sirt2), an NAD+-dependent lysine deacylase enzyme, has previously been implicated as a regulator of glucose metabolism, but the specific mechanisms remain poorly defined. Here, we observed that Sirt2-/- males, but not females, have decreased body fat, moderate hypoglycemia upon fasting, and perturbed glucose handling during exercise compared to wild type controls. Conversion of injected lactate, pyruvate, and glycerol boluses into glucose via gluconeogenesis was impaired, but only in males. Primary Sirt2-/- male hepatocytes exhibited reduced glycolysis and reduced mitochondrial respiration. RNAseq and proteomics were used to interrogate mechanisms behind this liver phenotype. Loss of Sirt2 did not lead to transcriptional dysregulation, as very few genes were altered in the transcriptome. In keeping with this, there was also negligible changes to protein abundance. Site-specific quantification of the hepatic acetylome, however, showed that 13% of all detected acetylated peptides were significantly increased in Sirt2-/- male liver versus wild type, representing putative Sirt2 target sites. Strikingly, none of these putative target sites were hyperacetylated in Sirt2-/- female liver. The target sites in male liver were distributed across mitochondria (44%), cytoplasm (32%), nucleus (8%), and other compartments (16%). Despite the high number of putative mitochondrial Sirt2 targets, Sirt2 antigen was not detected in purified wild type liver mitochondria, suggesting that Sirt2 regulation of mitochondrial function occurs from outside the organelle. We conclude that Sirt2 regulates hepatic protein acetylation and metabolism in a sex-specific manner.
2024-07-19 | MSV000095391 | MassIVE
Project description:Aberrant expression of IL-17A together with abated IL-2 production by effector CD4+ T cells contributes to the pathogenesis of systemic lupus erythematosus (SLE). Here we report that Sirtuin 2 (SIRT2), a member of the family of NAD+-dependent histone deacetylases, suppresses IL-2 production by CD4+ T cells while it promotes their differentiation into Th17 cells. Mechanistically, we show that SIRT2 is responsible for the deacetylation of p70S6K and the activation of the mTORC1/HIF-1α/RORγt pathway and the generation of Th17 cells differentiation. Additionally, SIRT2 is responsible for the deacetylation of c-Jun and histones on the Il-2 gene, resulting in decreased IL-2 production. We found that the transcription factor inducible cAMP early repressor (ICER), which is overexpressed in T cells from people with SLE and lupus-prone mice, binds directly to the Sirt2 promoter and promotes its transcription. AK-7, a SIRT2 inhibitor limited the ability of adoptively transferred antigen-specific CD4+ T cells to cause autoimmune encephalomyelitis and disease in the lupus-prone MRL/lpr mice. Finally, CD4+ T cells from SLE patients exhibited increased expression of SIRT2, and pharmacological inhibition of SIRT2 in primary CD4+ T cells from patients with SLE attenuated their ability to differentiate into Th17 cells and promoted IL-2–producing T cells. Collectively, these results suggest that SIRT2-mediated deacetylation is essential for the aberrant expression of IL-17A and IL-2 and that SIRT2 may be a promising molecular target for new therapies for SLE.
2022-03-30 | GSE199496 | GEO
Project description:We provide evidence for the essential role of Sirt2 in IFN mediated signaling. Our studies demonstrate that SIRT2 controls expression of key interferon stimulated genes (ISGs) that mediate important biological functions, including anti-viral and antineoplastic responses.
2015-12-31 | GSE66033 | GEO