Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Potentiation of Noncanonical NF- B Signaling and Marginal Zone B Cell Expansion by CARD11-mediated Regulation of p100 Processing

ABSTRACT: Caspase recruitment domain-containing protein 11 (CARD11) is a multi-domain scaffolding protein critical for the adaptive immune response that is required for antigen receptor signaling to canonical NF-kB, mTOR, JNK, and AKT. Oncogenic gain-of-function (GOF) CARD11 mutants, implicated in a variety of lymphomas, bypass normal regulation and signal constitutively. In a mouse model expressing the lymphoma-associated GOF mutation CARD11 C49Y, we observed splenomegaly concomitant with B cell expansion that was most pronounced for Marginal Zone (MZ) B cells. CARD11C49Y/C49Y MZ B cells exhibited enhanced cell-autonomous survivability and elevated basal levels of the precursor NF-kB subunit p100, which was inducibly processed, leading to elevated nuclear p52 levels in response to BAFF. We show in a heterologous assay that active CARD11 variants can inhibit basal NIK-induced p100 processing to p52 independently of their ability to activate canonical NF-kB. Our results reveal an unexpected ability of CARD11 GOF mutants to potentiate the noncanonical NF-kB pathway through p100 accumulation, which likely contributes to the dysregulated B cell expansion observed in lymphomas that harbor CARD11 GOF variants.

ORGANISM(S): Mus musculus

PROVIDER: GSE287097 | GEO | 2025/10/09

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Immune differentiation regulator p100 tunes NF-kB responses to TNF

Project description:Stringent regulation of TNF signaling prevents aberrant inflammation. TNF engages the canonical NF-kB pathway for activating the RelA:p50 heterodimer, which mediates specific expressions of pro-inflammatory and immune response genes. Importantly, the NF-kB system discriminates between time-varied TNF inputs. Negative feedback regulators of the canonical pathway, including IkBa, thought to ensure transient RelA:p50 responses to brief TNF stimulations. The noncanonical NF-kB pathway controls a separate RelB activity associated with immune differentiation. In a systems modeling approach, we uncovered an unexpected role of p100, a constituent of the noncanonical pathway, in TNF signaling. Brief TNF stimulation of p100-deficient cells produced an additional late NF-kB activity composed of the RelB:p50 heterodimer, which distorted the TNF-induced gene-expression program. Periodic TNF pulses augmented this RelB:p50 activity, which was reinforced by NF-kB-dependent RelB synthesis. In sum, the NF-kB system seems to engage distantly related molecular species for enforcing dynamical and gene controls of immune-activating TNF signaling.

2020-08-22 | GSE119961 | GEO

p100 deficiency alone is insufficient for full activation of the alternative NF-?B pathway: TNF signaling cooperates with p52-RelB activation in the transcriptional regulation of the enpp2/autotaxin promoter

Project description:Background: Constitutive activation of the alternative NF-?B pathway leads to marginal zone B cell expansion and disorganized spleen microarchitecture. Furthermore, uncontrolled alternative NF-?B signaling results in the development and progression of cancer. We aimed here to learn about the mechanisms how does the constitutively active alternative NF-?B pathway exert its effects in these malignant processes. Methodology/Principal Findings: To explore the consequences of constitutive alternative NF-?B activation on genome-wide transcription, we compared gene expression profiles of wild-type and NF-kB2/p100-deficient (p100-/-) primary mouse embryonic fibroblasts (MEFs) and spleens. Microarray experiments revealed 73 differentially regulated genes in p100-/- vs. wild-type MEFs. Chromatin immunoprecipitation (ChIP) assays showed in p100-/- MEFs direct binding of RelB and p52 to the promoter of the enpp2 gene encoding Enpp2/Autotaxin, a protein with an important role in lymphocyte homing and cell migration. Gene ontology analysis revealed upregulation of genes with anti-apoptotic/proliferative activity (enpp2, serpina3g, traf1, rrad), chemotactic/locomotory activity (enpp2, ccl8), and lymphocyte homing activity (enpp2, cd34). Most importantly, biochemical analyses of MEFs and gene expression analyses of mice indicated a crosstalk between classical and alternative NF-?B pathways. Conclusions/Significance: The present results show that uncontrolled alternative NF-?B signaling is further enhanced by classical NF-?B activation, indicating that p100 deficiency alone is insufficient for full induction of a subset of genes by the alternative NF-?B pathway. cell type comparison (wt vs p100-/-) after genetic modification

2012-12-21 | E-GEOD-30317 | biostudies-arrayexpress

Immune differentiation regulator p100 tunes NF-kB responses to TNF

Project description:Immune differentiation regulator p100 tunes NF-kB responses to TNF

| PRJNA490828 | ENA

p100 deficiency alone is insufficient for full activation of the alternative NF-κB pathway: TNF signaling cooperates with p52-RelB activation in the transcriptional regulation of the enpp2/autotaxin promoter

Project description:Background: Constitutive activation of the alternative NF-κB pathway leads to marginal zone B cell expansion and disorganized spleen microarchitecture. Furthermore, uncontrolled alternative NF-κB signaling results in the development and progression of cancer. We aimed here to learn about the mechanisms how does the constitutively active alternative NF-κB pathway exert its effects in these malignant processes. Methodology/Principal Findings: To explore the consequences of constitutive alternative NF-κB activation on genome-wide transcription, we compared gene expression profiles of wild-type and NF-kB2/p100-deficient (p100-/-) primary mouse embryonic fibroblasts (MEFs) and spleens. Microarray experiments revealed 73 differentially regulated genes in p100-/- vs. wild-type MEFs. Chromatin immunoprecipitation (ChIP) assays showed in p100-/- MEFs direct binding of RelB and p52 to the promoter of the enpp2 gene encoding Enpp2/Autotaxin, a protein with an important role in lymphocyte homing and cell migration. Gene ontology analysis revealed upregulation of genes with anti-apoptotic/proliferative activity (enpp2, serpina3g, traf1, rrad), chemotactic/locomotory activity (enpp2, ccl8), and lymphocyte homing activity (enpp2, cd34). Most importantly, biochemical analyses of MEFs and gene expression analyses of mice indicated a crosstalk between classical and alternative NF-κB pathways. Conclusions/Significance: The present results show that uncontrolled alternative NF-κB signaling is further enhanced by classical NF-κB activation, indicating that p100 deficiency alone is insufficient for full induction of a subset of genes by the alternative NF-κB pathway.

2012-12-21 | GSE30317 | GEO

Developmental LTbR synergistically activates TLR4 mediated inflammatory RelA/NF-kB response

Project description:Developmental signals are known to modulate inflammation. How ever, the mechanistic insight that links developmental and inflammatory signaling remains elusive. In the current study, we identifya critical role of NF-kB system in mediating stimulus specific crosstalk that allows developmental LTbR signals to sustain inflammatory TLR4 induced RelA/NF-kB response and gene expression. LTbR activated non-canonical signaling targets canonical TLR4 induced, nfkb2 encoded p100 not only to deplete inhibitory IkBd/(p100)2, but also to supplement RelA:p52/NF-kB dimers. Robust crosstalk in the gut epithelial cells are important, as crosstalk-defective nfkb2-/- mice succumbed to gut infection by Citrobacter rodentium due to hypo-inflammatory responses. Finally, we present evidence for a crosstalk motif that integrates tissue microenvironment derived developmental cues to ameliorate the pathogen response.

2015-05-01 | GSE62301 | GEO

Developmental LTbR synergistically activates TLR4 mediated inflammatory RelA/NF-kB response

2015-05-01 | E-GEOD-62301 | biostudies-arrayexpress

NFKB2 Knockdown Reduces Expression of HR-Related Genes

Project description:Homologous recombination (HR) serves multiple roles in DNA repair that are essential for maintaining genomic stability. The central HR protein, RAD51, is frequently overexpressed in human malignancies, thereby elevating HR proficiency and promoting resistance to DNA-damaging therapies. Here we find that non-canonical NF-κB factors control the expression of RAD51 andother HR-promoting proteins. Transcriptional silencing of p100/p52 reduces RAD51 protein levels in multiple human cancer subtypes. RNA-seq after p100/p52 silencing identifies RAD51 as the most differentially expressed gene among 40 genes with known relevance to HR. While p100/p52 depletion inhibits HR function in human tumor cells, it does not influence the function of other double-strand DNA repair pathways including single-strand annealing, microhomology mediated annealing, or non-homologous end joining.

2022-06-07 | GSE148511 | GEO

DLBCL-reminiscent MyD88- or CARD11-mutant aggressive B-cell lymphomas exhibit strong pro-senescent and immune-evasive phenotypes [part1]

Project description:Aberrant B-cell receptor (BCR)/NF-kB signaling activity is a prominent feature of diffuse large B-cell lymphoma (DLBCL), particularly of, but not restricted to the activated B-cell (ABC) subtype. Recurrent mutations in this cascade, e.g. in CD79B, CARD11, A20/TNFAIP3 or NFKBIZ, but also in the Toll-like receptor (TLR) pathway transducer MyD88, all converge at NF-kB deregulation, but their differential impact on lymphoma development and biology remains to be dissected. Recapitulating oncogenic myc rearrangements as another common feature of DLBCL, we functionally investigate here primary mouse lymphomas that formed after propagation of Eµ-myc transgenic hematopoietic stem cells (HSC), stably transduced with naturally occurring DLBCL-derived NF-kB mutants, in recipient mice. While most mutants tested supported Myc-driven lymphoma formation through repressed apoptosis, selectively deregulated CARD11- or MyD88-mutant lymphoma cells presented with a macrophage-activating secretion profile, which, in turn, enforced TGF-b-mediated feedback senescence in the lymphoma cell compartment. Moreover, MyD88- or CARD11-mutant Eµ-myc lymphomas – mirrored by matching signatures in their mutant DLBCL counterparts – exhibited high-level expression of the immune checkpoint mediator PD-L1, thus preventing their efficient clearance by adaptive host cell immunity. Conversely, these mutant-specific dependencies were therapeutically exploitable by anti-PD1 immune checkpoint blockade, leading to the direct T-cell-mediated lysis of predominantly but not exclusively senescent lymphoma cells. Our functional, cross-species interrogation of a syngeneic and fully immune-competent, BCR/NF-kB-deregulated and DLBCL-reminiscent in vivo-model platform unveils common principles and therapeutic vulnerabilities related to human DLBCL subsets that will inform future personalized treatment strategies.

2020-12-07 | GSE141452 | GEO

Oncogene-induced MALT1 protease activity drives post-transcriptional gene expression in malignant lymphomas

Project description:Constitutive MALT1 activity drives survival of malignant lymphomas addicted to chronic B-cell receptor (BCR) signaling, oncogenic CARD11, or the API2-MALT1 fusion oncoprotein. While MALT1 scaffolding induces NF-kB-dependent survival signaling, MALT1 protease function is thought to augment NF-kB activation by cleaving signaling mediators and transcriptional regulators in B-cell lymphomas. However, the pathological role of MALT1 protease function in lymphomagenesis is not well understood. Here, we show that TRAF6 controls MALT1-dependent activation of NF-kB transcriptional responses, but is dispensable for MALT1 protease activation driven by oncogenic CARD11. To uncouple enzymatic and non-enzymatic functions of MALT1, we analyzed TRAF6-dependent and -independent as well as MALT1 protease-dependent gene expression profiles downstream of oncogenic CARD11 and API2-MALT1. By cleaving and inactivating the RNA binding proteins Regnase-1 and Roquin-1/2, MALT1 protease induces post-transcriptional upregulation of genes like NFKBIZ/IkBz, NFKBID/IkBNS and ZC3H12A/Regnase-1 in activated B-cell-like diffuse large B-cell lymphoma (ABC DLBCL). We demonstrate that oncogene-driven MALT1 activity in ABC DLBCL cells regulates NFKBIZ and NFKBID induction on mRNA level via releasing a brake imposed by Regnase-1 and Roquin-1/2. Furthermore, MALT1 protease drives post-transcriptional gene induction in the context of the API2-MALT1 fusion created by the recurrent t(11;18)(q21;q21) translocation in mucosa-associated lymphoid tissue (MALT) lymphoma. Thus, MALT1 paracaspase acts as a bifurcation point for enhancing transcriptional and post-transcriptional gene expression in malignant lymphomas. Moreover, the identification of MALT1 protease selective target genes will provides specific biomarkers for the clinical evaluation of MALT1 inhibitors.

2023-08-25 | GSE215792 | GEO

IKKa-mediated signaling circuitry regulates early B lymphopoiesis during hematopoiesis

Project description:Multiple transcription factors regulate B cell commitment, which coordinates with myeloid–erythroid lineage differentiation. One such factor, NF-kB, has long been speculated to regulate early B cell development; however, this issue remains controversial. IKKa is required for splenic B cell maturation, but not for bone marrow (BM) B cell development. Here, we unexpectedly found defective BM B cell development and an increased myeloid–erythroid lineages in kinase-dead IKKa (KA/KA) knock-in mice. Markedly increased cytosolic p100, an NF-kB2 inhibitory form, and reduced nuclear NF-kB p65, RelB, p50, and p52, as well as IKKa, was observed in KA/KA splenic and BM B cells. Several B- and myeloid–erythroid-cell regulators, including Pax5, were deregulated in KA/KA BM B cells. Using fetal liver and BM congenic transplants, and IKKa deletion from early hematopoietic cells in mice, this defect was identified as B cell intrinsic and as an early event during hematopoiesis. Re-expression of IKKa, Pax5, or combined NF-kB molecules promoted B cell development, but repressed myeloid–erythroid cell differentiation in KA/KA BM B cells. Together, these results demonstrate that IKKa regulates B-lineage commitment via combined canonical and noncanonical NF-kB transcriptional activity to target Pax5 expression during hematopoiesis.

2011-07-02 | GSE30363 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

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