Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Non-apoptotic Fas signaling controls CD40 dependent mTOR activation and human B cell fate via PTEN nuclear exclusion

ABSTRACT: Defective Fas signaling causes autoimmune lymphoproliferative syndrome (ALPS). While defective apoptosis may impair negative selection and removal of autoreactive B lymphocytes, Fas transmits also non-apoptotic signals. We show herethat transient Fas ligation in CD40L-stimulated human B cells specifically decreased the mTOR axis activation without causing apoptosis. This signal modulation was absent in ALPS patients. Rather, mTOR signaling was enhanced in germinal center (GC) B cells and plasmablasts derived from a ALPS patient lymph node . Mechanistically, transient Fas engagement induced recruitment of DAXX to the activated Fas complex and nuclear exclusion of PTEN. Likewise, Fas stimulation promoted expression of transcripts like MYC and CXCR4, that regulate GC formation and fate decisions of established GC B cells. We suggest that non-apoptotic Fas signaling has a physiological impact on activated B cell fate decisions explaining the effectiveness of mTOR inhibitors in the treatment of ALPS autoimmunity.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Cell, Naive B Cell, Blood

DISEASE(S): Autoimmune Lymphoproliferative Syndrome

SUBMITTER: Marta Rizzi

LAB HEAD: Marta Rizzi

PROVIDER: PXD017601 | Pride | 2024-04-08

REPOSITORIES: Pride

ACCESS DATA

Json Xml

Similar Datasets

Label free mass spectrometry quantification of differentially expressed proteins in an atypical presentation of Autoimmune Lymphoproliferative Syndrome.

Project description:Autoimmune lymphoproliferative syndrome (ALPS) is a rare disease characterized among others things by chronic massive, nonmalignant lymphoadenopathy and splenomegaly. ALPS has been defined as a defect in the lymphocyte apoptotic pathway and is associate with inherited mutations in the FAS, Fas ligand and caspase 10 genes. However, 20-30% of the patients clinically diagnosed do not present any known mutations. We report here the case of a 10 years old girl with a probable diagnostic of ALPS. The patient meet the criteria of the disease nevertheless, the sequencing analysis of the genes involved did not present mutations. In order to go further in the knowledge of the ailment of this patient, we performed the study of the proteome of her peripheral blood mononuclear cells (PBMC) population. We compare the expression of proteins in the sample of the patient with a sample of a same years old healthy girl. The information achieved will provide us valuable elements to make a more integral diagnostic of ALPS and also, others autoimmune diseases.

2022-05-31 | PXD013289 | Pride

Mitochondrial respiration in B lymphocytes is essential for humoral immunity by controlling flux of the TCA cycle

Project description:The function of mitochondrial respiration during B cell fate decisions and differentiation 55 remained equivocal. This study reveals that selection for mitochondrial fitness occurs during B 56 cell activation and is essential for subsequent plasma cell differentiation. By expressing a 57 mutated mitochondrial helicase in transitional B cells, we depleted mitochondrial DNA during 58 B cell maturation, resulting in reduced oxidative phosphorylation. Although no changes in 59 follicular B cell development were evident, germinal centers, class switch recombination to 60 IgG, plasma cell maturation and humoral immunity were diminished. Defective oxidative 61 phosphorylation led to aberrant flux of the tricarboxylic acid cycle and lowered the amount of 62 saturated phosphatidic acid. Consequently, mTOR activity and BLIMP1 induction were 63 curtailed whereas HIF1 _and glycolysis were amplified. Exogenous phosphatidic acid 64 increased mTOR activity in activated B cells. Hence, mitochondrial function is required and 65 selected for in activated B cells for the successful generation of functional plasma cells.

2022-04-06 | ST002140 | MetabolomicsWorkbench

Transcription profiling of human peripheral blood mononuclear cells WITH a germline NRAS mutation vs controls reveals NRAScauses a novel human autoimmune lymphoproliferative syndrome (ALPS)

Project description:The p21 RAS subfamily of small GTPases, including KRAS, HRAS, and NRAS, regulates cell proliferation, cytoskeletal organization and other signaling networks, and is the most frequent target of activating mutations in cancer. Activating germline mutations of KRAS and HRAS cause severe developmental abnormalities leading to Noonan, cardio-facial-cutaneous and Costello syndrome, but activating germline mutations of NRAS have not been reported. Autoimmune lymphoproliferative syndrome (ALPS) is the most common genetic disease of lymphocyte apoptosis and causes autoimmunity as well as excessive lymphocyte accumulation, particularly of CD4-, CD8- ab T cells. Mutations in ALPS typically affect CD95 (Fas/APO-1)-mediated apoptosis, one of the extrinsic death pathways involving tumor necrosis factor receptor (TNFR) superfamily proteins, but certain ALPS individuals have no such mutations. We show here that the salient features of ALPS as well as a predisposition to hematological malignancies can be caused by a heterozygous germline Gly13Asp activating mutation of the NRAS oncogene that does not impair CD95-mediated apoptosis. The increase in active, GTP-bound NRAS augments RAF/MEK/ERK signaling which markedly decreases the pro-apoptotic protein BIM and attenuates intrinsic, nonreceptor-mediated mitochondrial apoptosis. Thus, germline activating mutations in NRAS differ from other p21 Ras oncoproteins by causing selective immune abnormalities without general developmental defects. Our observations on the effects of NRAS activation indicate that RAS-inactivating drugs, such as farnesyl-transferase inhibitors (FTIs) should be examined in human autoimmune and lymphocyte homeostasis disorders. Experiment Overall Design: Describes the discovery of a new gene underlying a novel type of autoimmune lymphoproliferative syndrome, and characterizes the mechanisms involved in the pathogenesis of the disease.

2008-04-04 | E-GEOD-7345 | biostudies-arrayexpress

Germline NRAS mutation causes a novel human autoimmune lymphoproliferative syndrome

2008-03-21 | GSE7345 | GEO

Regulation of PERK-eIF2Î± Signaling by Tuberous Sclerosis Complex-1 Controls Homeostasis and Survival of Myelinating Oligodendrocytes

Project description:Tuberous sclerosis complex (TSC), an autosomal dominant disorder caused by mutations in either TSC1 or TSC2, exhibits white matter abnormalities including CNS myelin deficits. however, underlying mechanisms are not fully understood. Here we find that, unexpectedly, constitutive activation of mTOR signaling caused by Tsc1 deletion in the oligodendrocyte lineage results in severe myelination defects and oligodendrocyte cell death. Expression profiling analysis reveals that Tsc1 ablation induces prominent endoplasmic reticulum (ER) stress responses through the PERKâeIF2Î± dependent signaling axis and activates Fas-JNK apoptotic pathways. Our studies suggest that TSC1-mTOR signaling acts as an important checkpoint for maintaining oligodendrocyte homeostasis. Gene expression profiling of optic nerve from P12 control and Tsc1cKO mice

2016-07-22 | E-GEOD-74893 | biostudies-arrayexpress

Regulation of PERK-eIF2α Signaling by Tuberous Sclerosis Complex-1 Controls Homeostasis and Survival of Myelinating Oligodendrocytes

Project description:Tuberous sclerosis complex (TSC), an autosomal dominant disorder caused by mutations in either TSC1 or TSC2, exhibits white matter abnormalities including CNS myelin deficits. however, underlying mechanisms are not fully understood. Here we find that, unexpectedly, constitutive activation of mTOR signaling caused by Tsc1 deletion in the oligodendrocyte lineage results in severe myelination defects and oligodendrocyte cell death. Expression profiling analysis reveals that Tsc1 ablation induces prominent endoplasmic reticulum (ER) stress responses through the PERK‐eIF2α dependent signaling axis and activates Fas-JNK apoptotic pathways. Our studies suggest that TSC1-mTOR signaling acts as an important checkpoint for maintaining oligodendrocyte homeostasis.

2016-07-22 | GSE74893 | GEO

Bach2 regulates B cell survival to maintain germinal centers and promote B cell memory

Project description:The transcription factor Bach2 serves as a crucial regulator of the germinal center (GC) reaction, which is required for production of high-affinity antibodies and establishment of long-lived B cell memory. However, the stage at which Bach2 controls the GC programs and the precise mechanism underlying these processes remain poorly understood. In this study, we show that genetic ablation of Bach2 in GC B cells of mice impairs their survival and maintenance, and memory B cell formation. These defects can be rescued by enforced expression of anti-apoptotic gene Bcl2. As expected, Bach2-deficient GC B cells are defective in antibody affinity maturation, but have normal somatic hyper mutation and class switch recombination of immunoglobulin genes. Mechanistically, Bach2 controls the GC programs by directly repressing pro-apoptotic gene Bim and a set of genes involved in cell stress response and metabolic processes. Thus, our work reveals the precise roles of Bach2 in the GC biology, and demonstrates that Bach2 acts as a crucial survival regulator of GC B cells, providing a key mechanism underlying GC B maintenance and B cell memory formation.

2022-06-05 | GSE205400 | GEO

Critical roles of Rictor/Sin1complexes in IFN-dependent Stat activation and generation of antiproliferative responses

Project description:We provide evidence that IFN-induced Stat-activation is defective in cells with targeted disruption of the Rictor gene, whose protein product is a key element of mTOR complex 2 (mTORC2). Our studies show that transient or stable knockdown of Rictor leads to decreased expression of several IFN-inducible genes that mediate important biological functions, including antiproliferative and pro-apoptotic responses. Rictor+/+ and Rictor-/- MEFs were treated with 2500 U/ml of mouse IFNα for 24 hours

2014-01-28 | E-GEOD-47896 | biostudies-arrayexpress

Spatiotemporal dynamics of Bach2 orchestrates B cell responses and fate decision

Project description:The molecular circuits that direct early T-dependent B cell responses and alternative cell-fate decisions remain poorly understood. Here, we show that either B cell receptor (BCR) or CD40 signals promoted mTORC1-dependent translation of the transcription factor Bach2. Transient up-regulation of Bach2 protein restrained activated B cell expansion and differentiation into plasma cell while promoting the germinal center (GC) and memory B cell fates at the pre-GC stage. However, enforced Bach2 expression facilitated memory B cell generation versus other cell fates. Mechanistically, Bach2 limited access of AP-1 factors and formed a reciprocal repression loop with IRF4. BCR and CD40 signals also down-regulated Bach2 transcript in antigen-activated B cells, and diversified its abundance in various effector populations, predisposing Bach2 protein expression and subsequent cell-fate choices during memory recall and GC reaction. Thus signaling-induced differential dynamics of Bach2 protein and mRNA in activated B cell control their cell-fate outcomes and imprint the fate of their descendant effector cells.

2021-07-18 | GSE180277 | GEO

Spatiotemporal dynamics of Bach2 orchestrates B cell responses and fate decision II

2022-06-08 | GSE180460 | 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