Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Screening for differentially expressed genes in patients with a novel immunodeficiency syndrome

ABSTRACT: Lysosome-related organelles have versatile functions including protein and lipid degradation, signal transduction, and protein secretion. The molecular elucidation of rare congenital diseases affecting endosomal/lysosomal biogenesis has given insights into physiological functions of the innate and adaptive immune system.. Here, we describe a novel human primary immunodeficiency disorder and provide evidence that the endosomal adaptor protein p14, previously characterized as confining mitogen-activated-protein-kinase (MAPK) signaling to late endosomes, is critical for the function of neutrophils, B-cells, cytotoxic T-cells and melanocytes. Combining genetic linkage studies and transcriptional profiling analysis, we identified a homozygous point mutation in the 3’ UTR of p14 (also known as MAPBPIP), resulting in decreased protein expression. In p14-deficient cells, the distribution of late endosomes was severely perturbed, suggesting a novel role for p14 in endosomal biogenesis. These findings have implications for understanding endosomal membrane dynamics, compartmentalization of cell signal cascades, and their role in immunity. Keywords: Interindividual comparison

ORGANISM(S): Homo sapiens

PROVIDER: GSE6322 | GEO | 2006/11/21

SECONDARY ACCESSION(S): PRJNA100585

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Transcription profiling of human EBV transformed cell lines established from patients with a novel immunodeficiency syndrome

Project description:Lysosome-related organelles have versatile functions including protein and lipid degradation, signal transduction, and protein secretion. The molecular elucidation of rare congenital diseases affecting endosomal/lysosomal biogenesis has given insights into physiological functions of the innate and adaptive immune system.. Here, we describe a novel human primary immunodeficiency disorder and provide evidence that the endosomal adaptor protein p14, previously characterized as confining mitogen-activated-protein-kinase (MAPK) signaling to late endosomes, is critical for the function of neutrophils, B-cells, cytotoxic T-cells and melanocytes. Combining genetic linkage studies and transcriptional profiling analysis, we identified a homozygous point mutation in the 3â UTR of p14 (also known as MAPBPIP), resulting in decreased protein expression. In p14-deficient cells, the distribution of late endosomes was severely perturbed, suggesting a novel role for p14 in endosomal biogenesis. These findings have implications for understanding endosomal membrane dynamics, compartmentalization of cell signal cascades, and their role in immunity. Experiment Overall Design: EBV-transformed B cell lines from 2 parents and 2 affected children

2008-06-14 | E-GEOD-6322 | biostudies-arrayexpress

Comprehensive proteomic and transcriptomic characterization of hepatic expression signatures affected in p14 liver conditional knockout mice

Project description:Scaffold proteins regulate intracellular MAP kinase signaling by providing critical spatial and temporal specificity. We have shown previously that the scaffold protein MEK1 partner (MP1) is localized to late endosomes by the adaptor protein p14. Using conditional gene disruption of p14 in livers of mice we analysed protein and transcript signatures in tissue samples. Further biological network analysis predicted that the differentially expressed transcripts and proteins are involved in cell cycle progression and regulation of cellular proliferation. Although some of the here identified signatures were previously linked to phospho-ERK activity, most of them were novel targets of late endosomal p14/MP1/MEK/ERK signaling module. Finally, the proliferation defect was confirmed in a chemically induced liver regeneration model in p14 liver knock-out mice. Conditional liver p14 KO mice were generated by mating p14 f/f mice with mice expressing Cre recombinase under control of Alb promoter and alpha-fetoprotein enhancer. The obtained p14 floxed/floxed;AlfpCre(p14 liver KO) mice were used in experiments as KO mice. To prevent the influence of AlfpCre transgene we used p14 +/+;AlfpCre mice as a control. All mice were derived in a C57BL/6 background and were six weeks old. Expression profiles of KO mouse samples were compared to expression profiles of corresponding control mice and differentially expressed genes were identified.

2011-02-01 | E-GEOD-24461 | biostudies-arrayexpress

Comprehensive proteomic and transcriptomic characterization of hepatic expression signatures affected in p14 liver conditional knockout mice

2011-02-01 | GSE24461 | GEO

Apolipoprotein E2 protects against aging-induced neuronal endosomal dysfunction through enhanced exosome secretion

Project description:In 12-month-old APOE targeted-replacement mice, we report that overall differences in gene expression were the most prominent when comparing the protective APOE2 to the other two alleles, with fewer differences found when comparing the risk-neutral APOE3 and disease-promoting APOE4 alleles. When compared with either APOE3 or APOE4, differential expression of genes within the endosomal pathways is a prominent feature of APOE2 expression in the brain. We hypothesized that the protective effects of APOE2 are mediated through the endosomal pathway during aging. In contrast to Alzheimer’s disease and APOE4 models, we detected normal morphology and abundance of early endosomes within cortical neurons of APOE2 targeted-replacement mice during aging despite decreased rab5b recruitment to early endosomes. Similarly, the morphology and abundance of retromer-associated vesicles was normal in APOE2 mice, despite reduced recruitment of vesicle-associated VPS35. Significantly, we observed increased brain extracellular levels of endosome-derived exosomes in APOE2 compared with APOE3 mice during aging, indicative of an enhanced endosomal cargo clearance to the extracellular space that contributes to a homeostatic balance of endosomal functions. Our findings thus demonstrate that APOE2 effectively offsets endosomal pathway changes during aging to preserve its integrity by enhancing exosome biogenesis, mitigating age-driven endosomal dysfunction that contributes to Alzheimer’s disease risk.

2023-07-31 | GSE188267 | GEO

PDZD8 interacts with Protrudin and Rab7 to form an ER-late endosome membrane contact site that recruits mitochondria

Project description:Endosomes regulate a plethora of cellular processes including signaling, nutrient status and organelle quality control by controlling the fate of material entering the cells. Endosomes undergo a process of maturation which specifies whether material will be shuttled back to the cell surface or degraded by the lysosome. Nevertheless, a complete inventory of factors regulating endosomal maturation is still lacking. Recently, membrane contact sites (MCSs) between the endoplasmic reticulum (ER) and endosomes have emerged as important players in endosomal sorting, dynamics and motility. Here, we identify the ER transmembrane protein PDZD8 as a new Rab7 effector that, together with the MCS component Protrudin, forms an ER-late endosome MCS. At these ER-late endosome MCSs, PDZD8 also recruits mitochondria to form a three-way contact. Our data suggest that the PDZD8/Protrudin-Rab7 MCS functions to facilitate an early stage of late endosome maturation.

2020-06-02 | PXD015523 | Pride

MITF drives endolysosomal biogenesis and potentiates Wnt signaling in melanoma cells

Project description:Canonical Wnt signaling plays an important role in development and disease, regulating transcription of target genes and stabilizing many proteins phosphorylated by Glycogen Synthase Kinase 3 (GSK3). We observed that the MiT family of transcription factors, which includes the melanoma oncogene MITF and the lysosomal master regulator TFEB, had the highest phylogenetic conservation of three consecutive putative GSK3 phosphorylation sites in animal proteomes. This prompted us to examine the relationship between MITF, endolysosomal biogenesis and Wnt signaling. Here we report that MITF expression levels correlated with the expression of a large subset of lysosomal genes in melanoma cell lines. MITF expression in the Tetracycline-inducible C32 melanoma model caused a marked increase in vesicular structures, and increased expression of late endosomal proteins such as Rab7, LAMP1, and CD63. These late endosomes were not functional lysosomes as they were less active in proteolysis, yet were able to concentrate Axin1, phospho-LRP6, phospho-β-Catenin, and GSK3 in the presence of Wnt ligands. This relocalization significantly enhanced Wnt signaling by increasing the number of multivesicular bodies (MVBs) into which the Wnt signalosome/destruction complex becomes localized upon Wnt signaling. We also show that the MITF protein was stabilized by Wnt signaling, through the novel C-terminal GSK3 phosphorylations identified here. MITF stabilization caused an increase in MVB biosynthesis, which in turn increased Wnt signaling, generating a positive feed-back loop that may function during the proliferative stages of melanoma. The results underscore the importance of misregulated endolysosomal biogenesis in Wnt signaling and cancer. Expression of selected Lysosomal genes and CLEAR element plus MITF were compared in 51 melanoma cell lines to a mixed reference pool containing equal amounts of 47 melanoma cell lines.

2014-12-24 | E-GEOD-64497 | biostudies-arrayexpress

GPCR endocytosis confers uniformity in responses to chemically distinct ligands

Project description:This study shows that chemically and pharmacodynamically distinct agonists acting on the same GPCR can produce indistinguishable cellular responses and that this uniformity is conferred by endosomal signaling The ability of chemically distinct ligands to produce different effects on the same G protein-coupled receptor (GPCR) has interesting therapeutic implications but, if excessively propagated downstream, would introduce biological 'noise' compromising cognate ligand detection We asked if cells have the ability to limit the degree to which chemical diversity imposed at the ligand-GPCR interface is propagated to the downstream signal We carried out an unbiased analysis of the integrated cellular response elicited by two chemically and pharmacodynamically diverse β-adrenoceptor agonists, isoproterenol and salmeterol We show that both ligands generate an identical integrated response, and that this stereotyped output requires endocytosis We further demonstrate that the endosomal β2-AR signal confers uniformity on the downstream response because it is highly sensitive and saturable Based on these findings, we propose that GPCR signaling from endosomes functions as a biological noise filter to enhance reliability of cognate ligand detection

2016-11-30 | GSE87461 | GEO

Microarray analysis of Arabidopsis ara6-1 mutant

Project description:Endosomal trafficking plays an integral role in various eukaryotic cell activities. In animal cells, a member of the RAB GTPase family, RAB5, is known as a key regulator of various endosomal functions, which include endosomal fusion, endosomal signaling, and endosomal motility. In addition to orthologs of animal RAB5, plants harbor the plant-unique RAB5 group, ARA6 group, which is conserved in all land plant lineages. The Arabidopsis genome encodes three RAB5 members: two conventional type RAB5 (ARA7 and RHA1) and one plant-specific ARA6. It has been already reported that ARA6 mediates a trafficking pathway from endosomes to the plasma membrane, and also shown to be involved in salt stress tolerance and flowering. However, physiological functions of ARA6 and their detailed mechanism are still remained elusive. In this study, we carried out a microarray analysis of the ara6-1 mutant. Possible involvement of ARA6 in sugar metabolism will be reported. The transcriptional profiling between the wild-type Col. and a RAB5 knock out mutant, ara6-1.

2015-02-18 | E-GEOD-57013 | biostudies-arrayexpress

A proximity interactome map of the VAC14-FIG4 complex using BioID

Project description:Conversion between phosphatidylinositol-3-phosphate and phosphatidylinositol-3,5-bisphosphate on endosomal membranes is critical for maturation of early endosomes to late endosomes/lysosomes, and is regulated by the PIKfyve-Vac14-Fig4 complex. In this study, we screened for the cellular interactome of Vac14 and Fig4 using proximity-dependent biotin labelling (BioID) in 293T cells.

2021-11-03 | PXD027917 | Pride

Reduced endosomal microautophagy activity in aging associates with enhanced exocyst-mediated protein secretion

Project description:Autophagy is essential for protein quality control and regulation of the functional proteome. Failure of autophagy pathways with age contributes to loss of proteostasis in aged organisms and accelerates progression of age-related diseases. In this work, we show that activity of endosomal microautophagy (eMI), a selective type of autophagy occurring in late endosomes, declines with age and identify the subproteome affected by this loss of function. Proteomics of late endosomes from old mice revealed an aberrant glycation signature for hsc70, the chaperone responsible for substrate targeting to eMI. Age-related hsc70 glycation reduces its stability in late endosomes by favoring its organization into high molecular weight protein complexes and promoting its internalization/degradation inside late endosomes. Reduction of eMI with age associates with an increase in protein secretion, as late endosomes can release protein-loaded exosomes upon plasma membrane fusion. Our search for molecular mediators of the eMI/secretion switch identified the exocyst-RalA complex, known for its role in exocytosis, as a novel physiological eMI inhibitor that interacts with hsc70 and acts directly at the late endosome membrane. This inhibitory function along with the higher exocyst-RalA complex levels detected in late endosomes from old mice could explain, at least in part, reduced eMI activity with age. Interaction of hsc70 with components of the exocyst-RalA complex places this chaperone in the switch from eMI to secretion. Reduced intracellular degradation in favor of extracellular release of undegraded material with age may be relevant to the spreading of proteotoxicity associated with aging and progression of proteinopathies.

2023-03-11 | PXD035128 | Pride

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