Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

CD28-CBCA driven PKM splicing licenses CD8 T cell glycolysis and effector function

ABSTRACT: T cells stimulated in the absence of CD28 costimulation are functionally anergic, characterized by reduced glucose metabolism and ability to produce effector cytokines. Surprisingly, previous studies have shown relatively few CD28-specific changes in gene transcription upon costimulation. Using mice expressing mutations in the CD28 cytoplasmic tail, we show a major effect of CD28 costimulation is alternative splicing of numerous genes including the glycolytic enzyme pyruvate kinase (Pkm), which is preferentially spliced from Pkm1 to Pkm2 upon stimulation. PKM2 is dispensable for T cell activation, but necessary for CD8+ T cells to utilize aerobic glycolysis, produce effector cytokines, and provide anti-tumor immunity. Mechanistically, CD28 regulates expression of the Cap-Binding Complex adaptor protein ARS2, which binds Pkm splicing factors and facilitates their interaction with the elongating transcript. Data suggest a major function of CD28 costimulation is control of RNA biogenesis in support of T cell transcriptome remodeling and acquisition of effector function.

ORGANISM(S): Mus musculus

PROVIDER: GSE168824 | GEO | 2023/09/01

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Germline loss of PKM2 promotes metabolic distress and hepatocellular carcinoma

Project description:Alternative splicing of the Pkm gene product generates the PKM1 and PKM2 isoforms of pyruvate kinase, and PKM2 expression is closely linked to embryogenesis, tissue regeneration, and cancer. To interrogate the functional requirement for PKM2 during development and tissue homeostasis, we generated germline PKM2 null mice (Pkm2-/-). Unexpectedly, despite being the primary isoform expressed in most wild-type adult tissues, we found that Pkm2-/- mice are viable and fertile. Thus, PKM2 is not required for embryonic or postnatal development. Loss of PKM2 leads to compensatory expression of PKM1 in the tissues that normally express PKM2. Strikingly, PKM2 loss leads to spontaneous development of hepatocellular carcinoma (HCC) with high penetrance that is accompanied by progressive changes in systemic metabolism characterized by altered systemic glucose homeostasis, inflammation, and hepatic steatosis. Therefore, in addition to its role in cancer metabolism, PKM2 plays a role in controlling systemic metabolic homeostasis and inflammation, thereby preventing HCC by a non-cell-autonomous mechanism. RNA was isolated from flash frozen ground whole liver tissue of 35 week old PKM2 KO and WT mice. Three independent mice from each condition were used as biological replicates.

2016-03-25 | E-GEOD-79535 | biostudies-arrayexpress

Germline loss of PKM2 promotes metabolic distress and hepatocellular carcinoma

2016-03-25 | GSE79535 | GEO

RBMX suppresses tumorigenicity and progression of bladder cancer via interaction with hnRNP A1 protein to regulate PKM alternative splicing

Project description:Bladder cancer (BCa) is one of the most common malignant tumors of urinary system and has high incidence rate and mortality but there is a lack of effective treatment. Therefore, an in-depth study of the molecular mechanisms involved in BCa is of great significance for improving the survival of patients with advanced BCa. We found that the expression of RBMX was significantly declined in BCa, especially in muscle-invasive BCa. BCa patients with low levels of RBMX had poor prognoses. By in vitro and in vivo experiments, RBMX was shown to inhibit BCa cells growth and metastasis. Co-IP coupled with MS and GO analysis identified hnRNP A1 as a RBMX-binding protein. Mechanistically, RBMX competitively bond to the RGG box of hnRNP A1 and antagonized the hnRNP A1-mediated regulation of PKM splicing by blocking the binding of the RGG motif of hnRNP A1 to the sequences flanking PKM exon 9, resulting in downregulation of PKM2 and upregulation of PKM1. By decreasing the PKM2/PKM1 ratio, RBMX suppressed BCa cells aerobic glycolysis, which further inhibited tumorigenicity and progression of BCa.

2020-11-23 | GSE150548 | GEO

Expression data from PKM1 or PKM2 expressing mouse embryonic fibroblasts.

Project description:We profiled global gene expression for two separate lines of mouse embryonic fibroblasts and find that deletion of PKM2 and expression of PKM1 does not alter global gene expression profiles. We used microarrays to futher characterize the effects of PKM1 expression compared to PKM2 expression on global gene expression in mouse embryonic fibroblasts. Primary mouse embryonic fibroblast cells were used for RNA extraction and hybridization on Affymetrix microarrays. Intensity files were RMA normalized using Affymetrix expression console.

2015-05-01 | E-GEOD-60499 | biostudies-arrayexpress

Expression data from PKM1 or PKM2 expressing mouse embryonic fibroblasts.

2015-05-01 | GSE60499 | GEO

Pyruvate kinase M1 and M2 isoform knock in ES cells differentiate into three germ layers

Project description:Analysis of wild type, PKm1 KI, and PKm2 KI ES cells.

2017-03-08 | GSE57504 | GEO

Analysis of Th17 gene signature in the presence of CD28 costimulation in human CD4 naïve T cells

Project description:We determined differentially regulated gene expression profile in CD4 naïve T cells cultured in presence or absence of Th17 inducing cytokines (IL23+IL1β) and anti-CD28. We reported that CD28 costimulation induced Th17-suppressive gene signature.

2018-03-12 | GSE110097 | GEO

Functional cross-talk between allosteric effects of activating and inhibiting ligands underlies PKM2 regulation.

Project description:Allosteric regulation is central to the role of the glycolytic enzyme pyruvate kinase M2 (PKM2) in cancer metabolism. Multiple activating and inhibitory allosteric ligands regulate PKM2 activity by controlling the equilibrium between high activity tetramers and low activity dimers and monomers. However, how allosteric inputs from simultaneous binding of different ligands are integrated to regulate PKM2 activity remains elusive. Here, we show that, [PKM2 activation and tetramerisation can be uncoupled as] in the presence of the allosteric inhibitor phenylalanine (Phe), saturating amounts of the activator fructose 1,6-bisphosphate (F-1,6-bP) can induce PKM2 tetramerisation, but fail to maximally increase enzymatic activity. We use a new computational framework to identify residues that mediate FBP-induced allostery and show that, while mutation of A327 and C358 do not abrogate the ability of F-1,6-BP to increase PKM2 activity, it prevents Phe from interfering with it. Our findings demonstrate a role for residues involved in FBP allostery in enabling the integration of allosteric input from Phe and reveal an allosteric cross-talk that underlies the co-ordinate regulation of PKM2 activity by distinct allosteric ligands. The absolute amount of the isoforms of PKM (PKM1/2) were quantified in the cell lines of interested to inform the described model.

2019-11-12 | PXD010334 | Pride

Interactomics of the RLTPR protein explain its essential role for costimulation via CD28

Project description:The RLTPR cytosolic protein has an essential role in CD28 costimulation but its mode of action and importance in human T cells remain elusive. Here, using mass spectrometry we showed that CD28, RLTPR and the CARMA1 cytosolic adaptor physically associate in mouse T cells. Although RLTPR is thought to function as an actin-uncapping protein, this property was dispensable for CD28 costimulation. Our findings underpin the convergent function of RLTPR in T cells and suggest that its scaffolding role predominates during CD28 costimulation.

2016-09-27 | PXD003870 | Pride

LncRNA GACAT2 binding protein PKM1/2 reverses inflammation-compromised mitochondrial function and cementoblastic differentiation of periodontal ligament stem cells

Project description:This study investigated the role of mitochondrial function and the downstream long noncoding RNAs (lncRNAs) in regulating inflammation-induced changes to the cementoblastic differentiation of PDLSCs. We found that inflammatory cytokine-caused impairment to cementoblastic differentiation of PDLSCs was closely correlated to their mitochondrial function, and in terms of lncRNA microarray analysis and gain/loss-of-function studies, gastric cancer associated transcript 2 (GACAT2) was identified as a regulator across the cellular events of both inflammation-mediated mitochondrial function and cementoblastic differentiation. Next, comprehensive identification of RNA-binding proteins by mass spectrometry (ChIRP-MS) and parallel reaction monitoring (PRM) assay revealed that GACAT2 was directly binded to protein pyruvate kinase M1/2 (PKM1/2). Further functional studies demonstrated that GACAT2 overexpression increased cellular protein expressions of PKM1/2, PKM2 tetramer and phosphorylated PKM2, led to an enhanced pyruvate kinase (PK) activity along with increased translocation of PKM2 into mitochondria. Finally, we found that GACAT2 overexpression could reverse inflammation-compromised mitochondrial function and cementoblastic differentiation of PDLSCs, and this function could be abolished by PKM1/2 knockdown. Our data suggest that lncRNA GACAT2 plays a critical role in inflammation-compromised mitochondrial function and cementoblastic differentiation by binding protein PKM1/2.

2022-03-23 | GSE176312 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data