ACC1-expressing pathogenic T helper 2 cell populations facilitate lung and skin inflammation
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE185743 | GEO | 2021/10/12
REPOSITORIES: GEO
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Project description:Acetyl-Coenzyme A (acetyl-CoA) is a central metabolite and the acetyl source for protein acetylation, particularly histone acetylation that promotes gene expression. However, the effect of acetyl-CoA levels on histone acetylation status in plants remains unknown. Here, we show that malfunctioned cytosolic acetyl-CoA carboxylase1 (ACC1) in Arabidopsis leads to elevated levels of acetyl-CoA and promotes histone hyperacetylation predominantly at lysine 27 of histone H3 (H3K27). The increase of H3K27 acetylation (H3K27ac) is dependent on ATP-citrate lyase which cleaves citrate to acetyl-CoA in the cytoplasm, and requires histone acetyltransferase GCN5. A comprehensive analysis of the transcriptome and metabolome in combination with the genome-wide H3K27ac profiles of acc1 mutants, demonstrate the dynamic changes of H3K27ac, gene transcripts and metabolites occurring in the cell by the increased levels of acetyl-CoA. This study suggests that H3K27ac is an important link between cytosolic acetyl-CoA level and gene expression in response to the dynamic metabolic environments in plants.
2017-09-25 | GSE79524 | GEO
Project description:Memory CD4+ T helper (Th) cells are crucial for acquired immunity and protection from infectious microorganisms, and also drive pathogenesis of chronic inflammatory diseases, such as asthma. ST2hi memory-type Th2 cells have been identified as a pathogenic subpopulation capable of directly inducing eosinophilic airway inflammation. These ST2hi pathogenic Th2 cells produce large amounts of IL-5 upon stimulation via their TCR, but not in response to IL-33. In contrast, IL-33 alone induces cytokine production in ST2+ group 2 innate lymphoid cells (ILC2). We investigated the molecular mechanism that controls the innate function of IL-33-induced cytokine production, and identified a MAPK phosphatase Dusp10, as a key negative regulator of IL-33–induced cytokine production in Th2 cells. We found that Dusp10 is expressed by ST2hi pathogenic Th2 cells but not by ILC2, and Dusp10 expression inhibits IL-33-induced cytokine production by preventing GATA3 activity through inhibition of p38 MAPK phosphorylation. Strikingly, deletion of Dusp10 rendered ST2hi Th2 cells able to directly respond to IL-33 exposure and produce IL-5. Thus, DUSP10 constrains IL-33–induced cytokine production in ST2hi pathogenic Th2 cells by controlling p38-mediated GATA3 function.
2018-09-23 | GSE116842 | GEO
Project description:Allergic responses in airway against house dust mites (HDMs) depend on lipid metabolism. However, whether the state of lipid metabolism in iNKT cells serves as a critical mechanism to impact development of allergic asthma remains elusive. Here, we showed that acetyl-CoA-Carboxylase 1 (ACC1), a key enzyme for fatty acid synthesis, was highly expressed in iNKT cells from asthmatic lungs. In ovalbumin (OVA)- and HDM-induced allergic asthma models, Cd4-CreAcc1fl/fl mice exhibited impaired homeostasis of iNKT cells and failed to develop AHR. ACC1-deficient iNKT cells reduced intracellular lipid concentration and expression of fatty acid binding proteins (FABPs) and peroxisome proliferator-activated receptor-gamma (PPAR-γ), whereas these cells were increased in glycolytic capacity. Moreover, ACC1-FABP-PPAR-γ axis regulated cell death of ACC1-deficient iNKT cells. Adoptive transfer of wild type (WT) iNKT cells restored AHR in Jɑ18 knockout mice in OVA or HDM-induced asthma models, whereas that of ACC1-deficient iNKT cells did not, indicating that fatty acid synthesis in iNKT cells is one of main contributors to the development of AHR. Our finding demonstrate fatty acid metabolism in iNKT cells is critical contributor for the development of AHR and airway inflammation in asthma.
2022-06-15 | GSE205761 | GEO
Project description:Metabolites are thought as the end products in cellular regulatory processes and their levels show the strongest relationships with the phenotype. Previously, we showed that the administration of Clostridium butyricum MIYAIRI 588 (CBM 588) upregulated protectin D1, an anti-inflammatory lipid metabolite, in colon tissue under antibiotic therapy. However, how CBM 588 induces protectin D1 expression and whether the metabolite has anti-inflammatory effects on antibiotic-induced inflammation are unclear. Therefore, here, we evaluated the effect of CBM 588 on lipid metabolism and protectin D1 in gut protection from antibiotic-induced intestinal disorders. In the CBM 588 treatment group, expression levels of genes encoding lipid receptors related to the conversion of DHA to protectin D1, such as polyunsaturated fatty acid (PUFA) receptors, G-protein coupled receptor 120 (GPR120), and 15-lipoxygenase (LOX), were increased in colon tissue. CD4+ cells producing interleukin (IL)-4, the main component of T helper type 2 (Th2) cells that can activate 15-LOX, also increased in CBM 588-treated groups even after clindamycin co-administration. In addition, similar to CBM 588, exogenously administered protectin D1 reduced inflammatory cytokines, while IL-10 and TGF-β1, works as anti-inflammatory cytokines, were increased. Our data revealed that CBM 588 activated 15-LOX to enhance protectin D1 production by increasing IL-4-producing CD4+ cell population in the intestinal tract. Additionally, CBM 588-induced protectin D1 clearly upregulated IL-10-producing CD4+ cells to control antibiotic-induced gut inflammation. We provide new insights into CBM 588-mediated lipid metabolism induction for the treatment of gut inflammatory diseases.
2020-10-14 | MTBLS2087 | MetaboLights
Project description:Th2 cell is a subset of CD4+ T helper (Th) cells, which regulates the immunity to extracellular parasites and allergic inflammation. Th2 cells specifically secrete Type 2 cytokines such as IL-4, IL-5, IL-13, and also express many universal cytokines like IL-2 and GM-CSF. While theses cytokines are indispensable for Th2 cell mediated response, there is complex heterogeneity in the pattern of cytokine production among Th2 cell population. As previous studies were mainly conducted at population levelref, here we took advantage of single-cell RNA-seq to explore heterogeneity in in vitro differentiated Th2 cells. Although a few single cell researches about Th2 cells was conducted, there is no comprehensive understanding of the heterogeneity of Th2 lineage yet, inspiring us to make some difference on this issue. Our studies identify that cytokine genes contributed most to the transcriptome heterogeneity of Th2 cells; expression of universal cytokines showed bimodality, but not Th2 specific cytokines.
2018-11-07 | GSE103647 | GEO
Project description:Protein post-translational modifications (PTMs) participate in important bioactive regulatory processes and therefore can help elucidate the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Here, we investigate the involvement of PTMs in ketogenic diet (KD)-improved fatty liver by multi-omics and reveal a core target of lysine malonylation, acetyl-CoA carboxylase 1 (ACC1). ACC1 protein levels and Lys1523 malonylation are significantly decreased by KD. It is discovered that a malonylation-mimic mutant in ACC1 increases its enzyme activity and stability to promote hepatic steatosis, whereas the malonylation-null mutant upregulates the ubiquitination degradation of ACC1. A customized Lys1523ACC1 malonylation antibody confirms the increased malonylation of ACC1 in the NAFLD samples. Overall, the lysine malonylation of ACC1 is attenuated by KD in NAFLD and plays an important role in promoting hepatic steatosis. Malonylation is critical for ACC1 activity and stability, highlighting the anti-malonylation effect of ACC1 as a potential strategy for treating NAFLD.
2023-03-05 | GSE226139 | GEO
Project description:Phosphatidylcholine (PC) is an abundant membrane lipid component in most eukaryotes including yeast. PC has been assigned a multitude of functions in addition to that of building block of the lipid bilayer. Here we show that PC is evolvable essential in yeast by isolating suppressor mutants devoid of PC that exhibit robust growth. The requirement for PC is suppressed by monosomy of chromosome XV, or by a point mutation in the ACC1 gene encoding acetyl-CoA carboxylase. Although these two genetic adaptations rewire lipid biosynthesis differently, both decrease Acc1 activity thereby reducing the average acyl chain length. Accordingly, soraphen A, a specific inhibitor of Acc1, rescues a yeast mutant with deficient PC synthesis. In the aneuploid suppressor, up-regulation of lipid synthesis is instrumental to accomplish feed-back inhibition of Acc1 by acyl-CoA produced by the fatty acid synthase (FAS). The results show that yeast regulates acyl chain length by fine-tuning the activities of Acc1 and FAS, and indicate that PC evolved by benefitting the maintenance of membrane fluidity.
2021-08-04 | GSE75725 | GEO
Project description:Protein post-translational modifications (PTMs) participate in important bioactive regulatory processes and therefore can help elucidate the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Here, we investigate the involvement of PTMs in ketogenic diet (KD)-improved fatty liver by multi-omics and reveal a core target of lysine malonylation, acetyl-CoA carboxylase 1 (ACC1). ACC1 protein levels and Lys1523 malonylation are significantly decreased by KD. It is discovered that a malonylation-mimic mutant in ACC1 increases its enzyme activity and stability to promote hepatic steatosis, whereas the malonylation-null mutant upregulates the ubiquitination degradation of ACC1. A customized Lys1523ACC1 malonylation antibody confirms the increased malonylation of ACC1 in the NAFLD samples. Overall, the lysine malonylation of ACC1 is attenuated by KD in NAFLD and plays an important role in promoting hepatic steatosis. Malonylation is critical for ACC1 activity and stability, highlighting the anti-malonylation effect of ACC1 as a potential strategy for treating NAFLD.
2023-07-21 | PXD040481 | Pride
Project description:Fatty acid synthesis is closely linked to nutrient availability and cellular energetic status. The committed step in fatty acid synthesis is the acetyl CoA carboxylase. Eukaryotes have two genes encoding acetyl CoA carboxylases, one encoding a cytosolic enzyme and another coding for a mitochondrial enzyme. They catalyze the synthesis of malonyl CoA in the cytosol and the mitochondria, respectively. While cytosolic malonyl CoA is the precursor for fatty acid synthesis, mitochondrial malonyl CoA controls the transfer of fatty acyl group into the mitochondria by inhibiting carnitine/palmitoyl transferase activity and thus, regulates β-oxidation. In Saccharomyces cerevisiae, β-oxidation is restricted to the peroxisomes, raising the question of the function of the mitochondrial isoform (HFA1). In this study, we replaced the cytosolic Acc1 with Hfa1 expressed in the cytosol by removing the mitochondrial leader peptide, under control of the HFA1 promoter. We studied fatty acid synthesis and transcription profiles in this strain during starvation for carbon or nitrogen, using glucose or ethanol as the carbon source. Under all the conditions studied, the key sensor of energetic status, Snf1, was activated, indicating active inhibition of fatty acid synthesis. The pool size of fatty acids was smaller when Acc1 was replaced with truncated Hfa1 for fatty acid synthesis. Yet, the transcription profiles were similar in both the cases. These results point towards the conclusion that Hfa1 is either catalytically less efficient or it is more sensitive to inhibition by Snf1. Gene expression from a strain of Saccharomyces cerevisiae where cytosolic fatty acid synthesis occurs by mitochondrial acetyl CoA carboxylase (without its mitochondrial leader peptide) is compared with that in a reference strain while growing in chemostats on carbon or nitrogen starvation using glucose or ethanol as the carbon source. There are two strains (reference or mutant), two carbon sources (glucose or ethanol) and two limitations (carbon or nitrogen), resulting in 8 comparisons. Each array was performed in duplicate, resulting in 16 CEL files. Growth was limited by either carbon or nitrogen. When carbon was the limited nutrient, we tested growth on either glucose or ethanol (both using ammonium sulfate as the nitrogen source). When ammonium sulfate was limiting, we used either glucose or ethanol as the carbon source.
2010-06-08 | E-GEOD-21988 | biostudies-arrayexpress
Project description:Interleukin-31 (IL-31), a T cells derived cytokine which is mainly produced by CD4+ T cells skewed towards Th2 phenotypes. It signals via a heterodimeric receptors composed of IL-31RA and OSMR that is expressed constitutively in epithelial cells and keratinocytes. IL-31 is shown to play a pathogenic role in allergic and inflammatory diseases. Transgenic mice overexpressing IL-31 have a phenotype similar to atopic dermatitis. Here, we studied the role of IL-31 in skin damage by intradermal administration of recombinant IL-31. Notably, IL-31 was sufficient to increase epidermal basal cell proliferation and thickening of the epidermal layer of skin in mice. Analysis of skin transcriptome indicates a significant increase in the transcripts involved in epidermal cell proliferation and pathological skin remodeling. Thus, our study revealed an important role of IL-31 signaling in activating transcriptional programs involved in the pathophysiology of skin diseases.
2016-03-19 | GSE79403 | GEO