Activated CARD11 accelerates germinal center kinetics, promoting mTORC1 and terminal differentiation.
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ABSTRACT:
PROVIDER: PRJNA483499 | ENA |
REPOSITORIES: ENA
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Project description:This scRNA-seq experiment is an integral part of a manuscript with the above title. Our analysis of the scRNA-seq data suggests that activated CARD11 promotes immunoglobulin class-switching in germinal center B cells and generation of IgG1-secreting plasma cells.
2018-07-31 | GSE117895 | GEO
Project description:Activating mutations in the adapter protein CARD11 associated with diffuse large B cell lymphomas (DLBCLs) are predicted to arise during germinal center (GC) responses, leading to inappropriate activation of NF-κB signaling. Here, we modeled the B cell-intrinsic impact of the L251P activating mutation in CARD11 (aCARD11) on the GC response. Global B cell aCARD11 expression led to a modest increase in splenic B cells and a severe reduction in B1 B cell numbers, respectively. Following T cell-dependent immunization, aCARD11 cells exhibited increased rates of GC formation, resolution, and differentiation. Restriction of aCARD11 to GC B cells similarly altered the GC response and B cell differentiation. In this model, aCARD11 promoted dark zone skewing along with increased cycling, AID levels, and class switch recombination. Furthermore, aCard11 GC B cells displayed increased biomass and mTORC1 signaling, suggesting a novel strategy for targeting aCARD11-driven DLBCL. While aCARD11 potently impacts GC responses, the rapid GC contraction suggests it requires collaboration with events that limit terminal differentiation to promote lymphoma.
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Project description:Activation of NFkB pathway by CARD11 Keywords: time series design
2006-03-30 | GSE3896 | GEO
Project description:Activation of NFkB pathway by CARD11 Cy3-labelled untreated sample and Cy5-labelled treated sample were hybridized to a Lymphochip microarray.
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Project description:A still unanswered question is what drives the small fraction of activated germinal center (GC) B cells that survive to become long-lived quiescent memory B cells. We found here that a small population of light zone GC cells (CD38intBcl6hi/intEfnb1+) with lower mTORC1 activity favored the memory B cell fate. Constitutively high mTORC1 activity led to defects in formation of the CD38intBcl6hi/intEfnb1+ cells; conversely, decreasing mTORC1 activity resulted in relative enrichment of this memory-prone GC population over the recycling-prone one. Furthermore, the CD38intBcl6hi/intEfnb1+ cells had higher levels of Bcl2 and surface BCR, which in turn, contributed to their survival. Given the positive correlation between the strength of T cell help and mTORC1 activity, our data suggest a model in which weak help from T cells together with provision of an increased survival signal are key for GC B cells to assume a memory B cell fate.
2020-09-13 | GSE147095 | GEO
Project description:A still unanswered question is what drives the small fraction of activated germinal center (GC) B cells that survive to become long-lived quiescent memory B cells. We found here that a small population of light zone GC cells (CD38intBcl6hi/intEfnb1+) with lower mTORC1 activity favored the memory B cell fate. Constitutively high mTORC1 activity led to defects in formation of the CD38intBcl6hi/intEfnb1+ cells; conversely, decreasing mTORC1 activity resulted in relative enrichment of this memory-prone GC population over the recycling-prone one. Furthermore, the CD38intBcl6hi/intEfnb1+ cells had higher levels of Bcl2 and surface BCR, which in turn, contributed to their survival. Given the positive correlation between the strength of T cell help and mTORC1 activity, our data suggest a model in which weak help from T cells together with provision of an increased survival signal are key for GC B cells to assume a memory B cell fate.
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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.
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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.
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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.
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