Browse
Submit Data
Databases
API
Help

Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Dendritic cells and stress translation

ABSTRACT: In response to inflammatory stimulation, dendritic cells (DCs) have a remarkable pattern of differentiation that exhibits specific mechanisms to control the immune response. Here we show that in response to polyriboinosinic:polyribocytidylic acid (poly I:C), DCs mount a specific transcription program during which the growth arrest and DNA damage-inducible protein 34 (GADD34/MyD116), a phosphatase 1 (PP1) cofactor, is expressed. Together with its constitutively active counterpart CReP, GADD34 promotes an extensive dephosphorylation of the translation initiation factor eIF2-alfa in activated DCs. In turn, dephosphorylation of eIF2-alfa prevents the translation inhibition normally associated with cellular stress or detection of cytoplasmic double-stranded RNA. These observations have important implications in linking pathogen detection with the integrated stress responses molecular machinery. The importance of this regulation for DC function is exemplified by the alteration of IFN-beta production or the induction of caspase-3 cleavage upon inhibition of PP1 activity. LPS-activated murine bone-marrow derived dendritic cells were transfected or pulsed with pIC and incubated for 4h or 16h. Cells were harvested, total RNA was extracted and analysed by Affymetrix microarrays analysis.

ORGANISM(S): Mus musculus

SUBMITTER: Philippe Pierre

PROVIDER: E-GEOD-18115 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

ACCESS DATA

Json Xml

Similar Datasets

Dendritic cells and stress translation

Project description:In response to inflammatory stimulation, dendritic cells (DCs) have a remarkable pattern of differentiation that exhibits specific mechanisms to control the immune response. Here we show that in response to polyriboinosinic:polyribocytidylic acid (poly I:C), DCs mount a specific transcription program during which the growth arrest and DNA damage-inducible protein 34 (GADD34/MyD116), a phosphatase 1 (PP1) cofactor, is expressed. Together with its constitutively active counterpart CReP, GADD34 promotes an extensive dephosphorylation of the translation initiation factor eIF2-alfa in activated DCs. In turn, dephosphorylation of eIF2-alfa prevents the translation inhibition normally associated with cellular stress or detection of cytoplasmic double-stranded RNA. These observations have important implications in linking pathogen detection with the integrated stress responses molecular machinery. The importance of this regulation for DC function is exemplified by the alteration of IFN-beta production or the induction of caspase-3 cleavage upon inhibition of PP1 activity.

2010-12-31 | GSE18115 | GEO

The Integrated Stress Response effector GADD34 is repurposed by neurons to promote stimulus-induced translation

Project description:Neuronal protein synthesis is required for long-lasting plasticity and long-term memory consolidation. Dephosphorylation of eukaryotic initiation factor 2α is one of the key translational control events that is required to increase de novo protein synthesis that underlies long-lasting plasticity and memory consolidation. Here, we interrogate the molecular pathways of translational control that are triggered by neuronal stimulation with brain-derived neurotrophic factor (BDNF), which results in eIF2α dephosphorylation and de novo protein synthesis. Primary rodent neurons exposed to BDNF displayed elevated translation, but not transcription, of GADD34, which facilitates eIF2α dephosphorylation and subsequent de novo protein synthesis. Furthermore, GADD34 requires G-actin generated by cofilin to dephosphorylate eIF2α and enhance protein synthesis. Finally, GADD34 is required for BDNF-induced translation of synaptic plasticity-related proteins. Overall, we provide evidence that neurons repurpose GADD34, an effector of the Integrated Stress Response, as an orchestrator of rapid increases in eIF2-dependent translation in response to plasticity-inducing stimuli.

2023-11-22 | GSE248013 | GEO

TFEB regulates protein synthesis to sustain autophagy during starvation

Project description:In response to starvation, cells undergo a metabolic shift to ensure their survival by shutting down protein synthesis and activating catabolic processes, including autophagy, to degrade proteins and recycle nutrients. These processes, however, do require protein synthesis. We asked how this fundamental conflict is resolved. Upon starvation, cells activate the Integrated Stress Response (ISR) and inhibit mammalian target of rapamycin complex 1 (mTORC1). The ISR inhibits protein translation through the phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2), whereas mTORC1 inhibition induces activation of the transcription factors TFEB/TFE3. We discovered that PPP1R15A (aka GADD34), a member of the protein phosphatase 1 complex (PP1) is a direct and early target of TFEB. GADD34 recruits PP1 to dephosphorylate eIF2 and thus fine-tunes protein synthesis to enable translation of the transcriptional program induced by starvation leading to a sustained autophagic flux.

2020-09-30 | PXD016149 | Pride

Response to poly(I:C) in WT and GADD34ΔC/ΔC MEFs

Project description:The stress-inducible GADD34 was shown to be induced during dsRNA sensing and is a stress-inducible PP1 cofactor responsible for dephosphorylation of translation initiation factor eIF2alpha. Its activity was shown to be required for efficient cytokine production in MEFs after poly(I:C) delivery. A microarray-based mRNA transcription analysis was used to compare the transcriptional response of WT and GADD34ΔC/ΔC MEFs lipofected with poly(I:C)

2017-01-16 | GSE77777 | GEO

Transcriptome profile of mouse lung dendritic cell subsets and macrophages.

Project description:Dendritic cell (DC) are critical initiators and regulators of immunity to pathogens, vaccines, tumors and tolerance to self. Mouse and human dendritic cells (DCs) are comprised of functionally specialized subsets, but precise interspecies correlation is currently incomplete and hampers the full translation of murine findings to human DC-based clinical therapies. In this study, we show that murine lung and gut lamina propria CD11b+ DC populations are comprised of two subsets: FLT3- and IRF4-dependent CD24+CD64- DCs and contaminating CSF-1R-dependent CD24-CD64+ macrophages. CD11b+CD24+CD64- DCs are instrumental in inducing Th17 cell immune response in the steady state and upon Aspergillus fumigatus challenge. We also identified human CD1c+CD11b+ DCs as the functional homologue of mouse mucosal CD11b+ DCs. Our findings highlight the conservation of key immune functions across species and aid the translation of murine studies to human DC immunobiology. The data for the associated human studies have been stored within GSE35459. Gene Expression from total RNA from specific mouse dendritic cell subsets purified by FACS

2013-05-29 | E-GEOD-46680 | biostudies-arrayexpress

Guanabenz effect on activated GM-CSF DCs

Project description:Guanabenz is an FDA approved drug for hypertension. It has been shown also to be an inhibitor of GADD34, the stress-inducible cofactor of PP1. GADD34 has been shown to play a key role in controlling cytokine production in MEFs and dendritic cells. A microarray-based mRNA transcription analysis was used to compare the transcriptional response of GM-CSF DCs, activated with poly I:C or Proteus mirabilis, in presence or absence of 50µM Guanabenz.

2017-08-15 | GSE90831 | GEO

Control of RNA pol II speed by PNUTS-PP1 and Spt5 dephosphorylation facilitates termination by a “sitting duck torpedo” mechanism

Project description:Control of transcription speed, which influences many co-transcriptional processes, is poorly understood. We report that PNUTS-PP1 phosphatase is a negative regulator of RNA pol II elongation rate. The PNUTS W401A mutation, which disrupts PP1 binding, causes genome-wide acceleration of transcription associated with hyper-phosphorylation of the Spt5 elongation factor. Immediately downstream of poly(A) sites, pol II decelerates from >2kb/min to <1 kb/min, which correlates with Spt5 dephosphorylation. Pol II deceleration and Spt5 dephosphorylation require poly(A) site recognition and the PNUTS-PP1 complex, which is in turn necessary for transcription termination. These results lead to a new model for termination, the “sitting duck torpedo” mechanism, where poly(A) site-dependent deceleration caused by PNUTS-PP1 and Spt5 dephosphorylation is required to convert pol II into a viable target for the Xrn2 terminator exonuclease. Spt5 and its bacterial homologue NusG therefore have related functions controlling kinetic competition between RNA polymerases and the termination factors that pursue them.

2019-10-30 | GSE134198 | GEO

Fine-tuning of human dendritic cells regulation revealed by translational profiling

Project description:Dendritic cells (DCs) are the sentinels of the mammalian immune system and they undergo a complex maturation process mediated by activation upon pathogen detection. Recent studies described the analysis of activated DCs by transcriptional profiling, but translation regulation was never taken in account. Therefore, the nature of the mRNAs being translated at various stages of DC activation was determined with the help of translational profiling, which is the sucrose gradient fractionation of polysomal-bound mRNAs combined to microarrays analysis. Total and polysomal-bound mRNA populations were compared in immature (0h) and LPS-stimulated (4h and 16h) human monocyte-derived DCs with the help of Affymetrix microarrays. Biostatistical analysis indicated that 296 mRNA molecules are translationally regulated during DC-activation. The most abundant biological process among the regulated mRNAs was protein biosynthesis, indicating the existence of a negative feedback loop regulating translation. Interestingly, a cluster of 17 ribosomal proteins were part of the regulated mRNAs, indicating that translation may be fine-tuned by particular components of the translational machinery. Our observations highlight the importance of translation regulation during the immune response, and may favour the identification of novel gene clusters or protein networks relevant for immunity. Our study also provides information on the possible absence of correlation between gene expression and real protein production in DCs.

2009-12-31 | GSE14000 | GEO

Combinatorial analyis of translation dynamics reveals eIF2 dependence of translation initiation at near-cognate codons

Project description:Although ribosome-profiling and translation initiation sequencing (TI-seq) analyses have identified many noncanonical initiation codons, the precise detection of translation initiation sites (TISs) remains a challenge, mainly because of experimental artifacts of such analyses. Here we describe a new method, TISCA (TIS detection by translation Complex Analysis), for the accurate identification of TISs. TISCA proved to be more reliable for TIS detection compared with existing tools, and it identified a substantial number of near-cognate codons in Kozak-like sequence contexts. Analysis of proteomics data revealed the presence of methionine at the NH2-terminus of most proteins derived from near-cognate initiation codons. Although eukaryotic initiation factor 2 (eIF2), eIF2A, and eIF2D have previously been shown to contribute to translation initiation at near-cognate codons, we found that most noncanonical initiation events are dependent on eIF2, consistent with the initial amino acid being methionine. Comprehensive identification of TISs by TISCA should facilitate characterization of the mechanism of noncanonical initiation.

2021-07-01 | GSE174329 | GEO

Ribosome profiling data obtained from HEK293T cells 30 minutes after treatment with arsenite to a final concentration of 40 M-BM-5M

Project description:Eukaryotic cells rapidly reduce protein synthesis in response to various stress conditions. This can be achieved by the phosphorylation-mediated inactivation of a key translation initiation factor, eIF2. However, the persistent translation of certain mRNAs is required for deployment of an adequate stress response. We carried out ribosome profiling of cultured human cells under conditions of severe stress induced with sodium arsenite. Although this led to a ~4.5-fold general translational repression, the protein coding ORFs of certain individual mRNAs exhibited resistance to the inhibition. Nearly all resistant transcripts possess at least one efficiently translated uORF that repress translation of the main coding ORF under normal conditions. Site specific mutagenesis of two identified stress resistant mRNAs (PPP1R15B and IFRD1) demonstrated that a single uORF is sufficient for eIF2-mediated translation control in both cases. Phylogenetic analysis suggests that at least two regulatory uORFs (namely in SLC35A4 and MIEF1) encode functional protein products. Ribosome profiling of sodium arsenite treated cells for examination of translational response to induction of eIF2 phosphoylation

2015-01-27 | E-GEOD-55195 | biostudies-arrayexpress

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