Dominant interfering CARD11 variants disrupt JNK signaling to promote GATA3 expression in T cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1217020 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Several “primary atopic disorders” are linked to monogenic defects that attenuate TCR signaling, favoring T helper 2 (TH2) cell differentiation. Patients with CARD11-associated atopy with dominant interference of NF-κB signaling (CADINS) disease suffer from severe atopy, caused by germline loss-of-function/dominant interfering (LOF/DI) CARD11 variants. The CARD11 scaffold enables TCR-induced activation of NF-κB, mTORC1, and JNK signaling, yet the function of CARD11-dependent JNK signaling in T cells remains nebulous. Here we show that CARD11 is critical for TCR-induced activation of JNK1 and JNK2, as well as canonical JUN/FOS AP-1 family members. Patient-derived CARD11 DI variants attenuated wild-type CARD11 JNK signaling, mirroring effects on NF-κB. Transcriptome profiling revealed JNK inhibition upregulated TCR-induced expression of GATA3 and NFATC1, key transcription factors for TH2 cell development. Further, impaired CARD11-JNK signaling was linked to enhanced GATA3 expression in CADINS patient T cells. Our findings reveal a novel intrinsic mechanism connecting impaired CARD11-dependent JNK signaling to enhanced GATA3/NFAT2 induction and TH2 cell differentiation in CADINS patients.
2025-02-28 | GSE288360 | GEO
Project description:Antigen receptor signaling pathways that control lymphocyte activation depend upon signaling hubs and negative regulatory proteins to fine-tune signaling output to ensure host defense and avoid potentially pathogenic hyperresponses. CARD11 is a critical signaling scaffold that translates T Cell Receptor triggering into the activation of branching NF-kB, JNK, mTOR and Akt pathways. Here we identify QRICH1 as a regulator of CARD11 signaling that mediates a previously undiscovered intracellular checkpoint for CD8+ T cell activation. QRICH1 inducibly associates with CARD11 following TCR engagement and negatively regulates CARD11 signaling to the IKK complex and NF-kB. QRICH1 binding to CARD11 occurs after TCR-induced CARD11 opening and is controlled by an autoregulatory intramolecular interaction between QRICH1 protein domains of previously uncharacterized function. Using mice deficient in QRICH1 in the T cell lineage, we show that QRICH1 controls the antigen-induced activation, proliferation, and effector status of CD8+ T cells by regulating numerous gene targets critical for CD8+ T cell function. Our results define a previously unappreciated component of antigen receptor signaling circuitry that fine-tunes effector output in response to antigen recognition.
2025-01-28 | GSE280713 | GEO
Project description:Activation of NFkB pathway by CARD11 Cy3-labelled untreated sample and Cy5-labelled treated sample were hybridized to a Lymphochip microarray.
2010-07-01 | E-GEOD-3896 | biostudies-arrayexpress
Project description:Estrogen Receptor (ER) is a steroid hormone receptor that regulates epithelial genes in breast cancer. ER forms a regulatory network with the other transcription factors, FOXA1 and GATA3. GATA3 is known to be capable of specifying chromatin localization of FOXA1 and ER. GATA3 has been identified as one of the most frequently mutated genes in breast cancer. However, how GATA3 mutations impact this transcriptional network is unknown. Here we investigate the function of one of the recurrent patient-derived GATA3 mutations (R330fs) for this regulatory network. Genomic analysis indicates that the R330fs mutant can disrupt the cooperative action of ER, FOXA1, and GATA3, and induce chromatin relocalization of these factors. Relocalizations of ER and FOXA1 are associated with altered chromatin architectures leading to differential gene expression in the GATA3 mutant cells. These results suggest the active role of GATA3 mutants in ER positive breast tumors.
2020-02-27 | GSE130703 | GEO
Project description:Activation of NFkB pathway by CARD11 Keywords: time series design
2006-03-30 | GSE3896 | GEO
Project description:In order to investigate the molecular mechanism of CARD11 in immune cell system, we applied the RNA-seq analysis using RNA isolated from WT and CARD11 mutant (E134G and K215M) mouse spleen B cells. By comparing the transcriptome files, we found some different expressed gene involved in due to the CARD11 point mutation and in vitro RT-PCR had confirmed this result.
2020-01-27 | GSE136588 | GEO
Project description:CARD11 LOF mutant patients develop severe atopic phenotpes and increased T-helper 2 (Th2) cytokine production, in addition to other immunopathology. CARD11 LOF impairs lymphocyte receptor–mediated glutamine uptake—thereby reducing signaling in mTORC1. Herein, we investigate whether exogenous glutamine treatment would alleviate Th2 phenotypes of CARD11 LOF mutant T cells.
2025-01-20 | GSE287077 | GEO
Project description:Background: The androgen receptor (AR) is a tumor suppressor in estrogen receptor (ER) positive breast cancer, a role sustained in some ER negative breast cancers. Key factors dictating AR genomic activity in a breast context are largely unknown. Herein, we employed an unbiased chromatin immunoprecipitation-based proteomic technique to identify endogenous AR interacting co-regulatory proteins in ER positive and negative models of breast cancer to gain new insight into mechanisms of AR signaling in this disease. Results: The DNA-binding factor GATA3 is identified and validated as a novel AR interacting protein in breast cancer cells irrespective of ER status. AR activation by the natural ligand 5α-dihydrotestosterone (DHT) increases nuclear AR-GATA3 interactions, resulting in AR-dependent enrichment of GATA3 chromatin binding at a sub-set of genomic loci. Silencing GATA3 reduces but does not prevent AR DNA binding and transactivation of genes associated with AR/GATA3 co-occupied loci, indicating a co-regulatory role for GATA3 in AR signaling. DHT-induced AR/GATA3 binding coincides with upregulation of luminal differentiation genes, including EHF and KDM4B, established master regulators of a breast epithelial cell lineage. These findings are validated in a patient-derived xenograft model of breast cancer. Interaction between AR and GATA3 is also associated with AR-mediated growth inhibition in ER positive and ER negative breast cancer.
2024-01-30 | PXD047997 | Pride
Project description:We describe the use of saturation genome editing to measure the effects of CARD11 variants on protein function, splicing and lymphoma cell survival. We find the results to predict the clinical effects of the variants.
2020-07-01 | GSE152129 | GEO
Project description:The immune system plays a critical role in inflammation by initiating responses to infection or tissue damage. NF-κB pathway plays a key role in inflammation and innate immunity, as well as other cellular activities. Furthermore, dysregulation of this well-choreographed pathway has been observed in many diseases, including cancer. CARD11 is a key molecule in the BCL-10, MALT1 (CBM) complex which is involved in transducing the signal downstream of the NF-κB pathway. This study aims to understand how overexpression of CARD11 adversely affects the prognosis in colorectal cancer (CRC) as it progresses towards aggressive form of the disease and the role that CARD11 plays in modulating the immune response across the different stages of CRC. To identify some of the cellular pathways activated as a result of CARD11, whole tran-scriptomics analysis was carried comparing the transcriptomic profile of CARD11-overexpressed HCT-116 and HT-29 CRC cell lines with empty vector-transfected cell lines as well as comparing adenoma and carcinoma CRC patients with CARD11- and CARD11+ expression. The whole tran-scriptomics and bioinformatics analysis results strongly suggested that CARD11 appears to play a key role in CRC progression. Absolute Gene Set Enrichment Analysis (absGSEA) on HCT-116 transcriptomics data showed that CARD11 overexpression promotes cell growth, and tissue re-modeling as well as enhancing the cell’s immune response. Some of the underlying genes in-volved in such processes through co-expression with CARD11 include EP300, KDM5A, HIF1A, NFKBIZ, and DUSP1. Results for HT-29 showed that CARD11 overexpression induces chemotaxis and ECM organization pathways through co-expression of IL1RN, MDK, and SPP1 as well as var-ious chemokines including CXCL1, CXCL3 and CCL22 which were shown to contribute to the more invasive stage of CRC. For patients, the adenoma patients include genes related to tumour immune microenvironment such as IL6ST, genes related to collagen family as well as other genes related to transition to CRC such as GLI3 and PIEZO2. While carcinoma patients show dramatic increase in the expression of MAPK8IP2 in CARD11+ carcinoma patients in addition to other genes related to cancer processes including EMB, EPHB6, and CPEB4. Taken together, the results show that CARD11 overexpression contributes to the progression of CRC through modu-lation of various tumour immune microenvironment pathways and activation of cancer path-ways possibly via the dysregulation of NF-κB. To our knowledge, this is probably the first study that investigates the role of CARD11 in CRC and the genes and pathways associated with CARD11 overexpression may provide insights into the early diagnostic and possible therapeutic targets for CRC.
2024-07-31 | GSE266390 | GEO