scholarly journals The E3 ubiquitin ligase Mule acts through the ATM–p53 axis to maintain B lymphocyte homeostasis

2012 ◽  
Vol 209 (1) ◽  
pp. 173-186 ◽  
Author(s):  
Zhenyue Hao ◽  
Gordon S. Duncan ◽  
Yu-Wen Su ◽  
Wanda Y. Li ◽  
Jennifer Silvester ◽  
...  
Keyword(s):  
Steady State ◽  
B Cells ◽  
B Cell ◽  
Ubiquitin Ligase ◽  
B Lymphocyte ◽  
E3 Ubiquitin Ligase ◽  
Genotoxic Stress ◽  
Cell Development ◽  
B Cell Development ◽  
Lymphocyte Homeostasis

Cellular homeostasis is controlled by pathways that balance cell death with survival. Mcl-1 ubiquitin ligase E3 (Mule) is an E3 ubiquitin ligase that targets the proapoptotic molecule p53 for polyubiquitination and degradation. To elucidate the role of Mule in B lymphocyte homeostasis, B cell–specific Mule knockout (BMKO) mice were generated using the Cre–LoxP recombination system. Analysis of BMKO mice showed that Mule was essential for B cell development, proliferation, homeostasis, and humoral immune responses. p53 transactivation was increased by two- to fourfold in Mule-deficient B cells at steady state. Genetic ablation of p53 in BMKO mice restored B cell development, proliferation, and homeostasis. p53 protein was increased in resting Mule-deficient mouse embryonic fibroblasts (MEFs) and embryonic stem (ES) cells. Loss of Mule in both MEFs and B cells at steady state resulted in increased levels of phospho–ataxia telangiectasia mutated (ATM) and the ATM substrate p53. Under genotoxic stress, BMKO B cells were resistant to apoptosis, and control MEFs exhibited evidence of a physical interaction between Mule and phospho-ATM. Phospho-ATM, phospho-p53, and Brca1 levels were reduced in Mule-deficient B cells and MEFs subjected to genotoxic stress. Thus, Mule regulates the ATM–p53 axis to maintain B cell homeostasis under both steady-state and stress conditions.

scholarly journals Ligand-independent Signaling Functions for the B Lymphocyte Antigen Receptor and Their Role in Positive Selection during B Lymphopoiesis

2001 ◽  
Vol 194 (11) ◽  
pp. 1583-1596 ◽  
Author(s):  
Gregory Bannish ◽  
Ezequiel M. Fuentes-Pananá ◽  
John C. Cambier ◽  
Warren S. Pear ◽  
John G. Monroe
Keyword(s):  
B Cells ◽  
B Cell ◽  
B Lymphocyte ◽  
Antigen Receptor ◽  
Cell Development ◽  
B Cell Development ◽  
B Lymphopoiesis ◽  
Biologically Relevant ◽  
Developmental Progression

Signal transduction through the B cell antigen receptor (BCR) is determined by a balance of positive and negative regulators. This balance is shifted by aggregation that results from binding to extracellular ligand. Aggregation of the BCR is necessary for eliciting negative selection or activation by BCR-expressing B cells. However, ligand-independent signaling through intermediate and mature forms of the BCR has been postulated to regulate B cell development and peripheral homeostasis. To address the importance of ligand-independent BCR signaling functions and their regulation during B cell development, we have designed a model that allows us to isolate the basal signaling functions of immunoglobulin (Ig)α/Igβ-containing BCR complexes from those that are dependent upon ligand-mediated aggregation. In vivo, we find that basal signaling is sufficient to facilitate pro-B → pre-B cell transition and to generate immature/mature peripheral B cells. The ability to generate basal signals and to drive developmental progression were both dependent on plasma membrane association of Igα/Igβ complexes and intact immunoregulatory tyrosine activation motifs (ITAM), thereby establishing a correlation between these processes. We believe that these studies are the first to directly demonstrate biologically relevant basal signaling through the BCR where the ability to interact with both conventional as well as nonconventional extracellular ligands is eliminated.

scholarly journals The E3 ubiquitin ligase Itch is required for B-cell development

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Xiaoling Liu ◽  
Yu Zhang ◽  
Yinxiang Wei ◽  
Zhiding Wang ◽  
Gaizhi Zhu ◽  
...  
Keyword(s):  
B Cell ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Cell Development ◽  
B Cell Development

scholarly journals The B29 (Immunoglobulin β-Chain) Gene Is a Genetic Target for Early B-Cell Factor

1999 ◽  
Vol 19 (1) ◽  
pp. 392-401 ◽  
Author(s):  
Peter Åkerblad ◽  
Maria Rosberg ◽  
Tomas Leanderson ◽  
Mikael Sigvardsson
Keyword(s):  
Transcription Factor ◽  
B Cells ◽  
B Cell ◽  
B Lymphocyte ◽  
Ectopic Expression ◽  
Cell Receptor ◽  
Cell Development ◽  
B Cell Development ◽  
Chain Gene ◽  
Early B Cell Factor

ABSTRACT Early B-cell factor (EBF) is a transcription factor suggested as essential for early B-lymphocyte development by findings in mice where the coding gene has been inactivated by homologous disruption. This makes the identification of genetic targets for this transcription factor pertinent for the understanding of early B-cell development. The lack of B29 transcripts, coding for the β subunit of the B-cell receptor complex, in pro-B cells from EBF-deficient mice suggested that B29 might be a genetic target for EBF. We here present data suggesting that EBF interacts with three independent sites within the mouse B29 promoter. Furthermore, ectopic expression of EBF in HeLa cells activated a B29promoter-controlled reporter construct 13-fold and induced a low level of expression from the endogenous B29 gene. Finally, mutations in the EBF binding sites diminished B29 promoter activity in pre-B cells while the same mutations did not have as striking an effect on the promoter function in B-cell lines of later differentiation stages. These data suggest that the B29gene is a genetic target for EBF in early B-cell development.

scholarly journals Regulation of B Lymphocyte Development by Histone H2A Deubiquitinase BAP1

2021 ◽  
Vol 12 ◽  
Author(s):  
Yun Hsiao Lin ◽  
Yue Liang ◽  
HanChen Wang ◽  
Lin Tze Tung ◽  
Michael Förster ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Cycle Progression ◽  
B Lymphocyte ◽  
Cell Development ◽  
B Cell Development ◽  
Lymphocyte Development ◽  
A Cell ◽  
B Lymphocyte Development

BAP1 is a deubiquitinase (DUB) of the Ubiquitin C-terminal Hydrolase (UCH) family that regulates gene expression and other cellular processes, via deubiquitination of histone H2AK119ub and other substrates. BAP1 is an important tumor suppressor in human, expressed and functional across many cell-types and tissues, including those of the immune system. B lymphocytes are the mediators of humoral immune response, however the role of BAP1 in B cell development and physiology remains poorly understood. Here we characterize a mouse line with a selective deletion of BAP1 within the B cell lineage (Bap1fl/fl mb1-Cre) and establish a cell intrinsic role of BAP1 in the regulation of B cell development. We demonstrate a depletion of large pre-B cells, transitional B cells, and mature B cells in Bap1fl/fl mb1-Cre mice. We characterize broad transcriptional changes in BAP1-deficient pre-B cells, map BAP1 binding across the genome, and analyze the effects of BAP1-loss on histone H2AK119ub levels and distribution. Overall, our work establishes a cell intrinsic role of BAP1 in B lymphocyte development, and suggests its contribution to the regulation of the transcriptional programs of cell cycle progression, via the deubiquitination of histone H2AK119ub.

scholarly journals Defective nonhomologous end joining blocks B-cell development in FLT3/ITD mice

Blood ◽  
2011 ◽  
Vol 117 (11) ◽  
pp. 3131-3139 ◽  
Author(s):  
Li Li ◽  
Li Zhang ◽  
Jinshui Fan ◽  
Kathleen Greenberg ◽  
Stephen Desiderio ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
B Lymphocyte ◽  
Cell Development ◽  
B Cell Development ◽  
Nonhomologous End Joining ◽  
End Joining ◽  
Lower Efficiency ◽  
Vdj Recombination ◽  
Nhej Pathway

Abstract We have generated an FLT3/ITD knock-in mouse model in which mice with an FLT3/ITD mutation develop myeloproliferative disease (MPD) and a block in early B-lymphocyte development. To elucidate the role of FLT3/ITD signaling in B-cell development, we studied VDJ recombination in the pro-B cells of FLT3/ITD mice and discovered an increased frequency of DNA double strand breaks (DSBs) introduced by the VDJ recombinase. Early pro-B cells from FLT3/ITD mice were found to have a lower efficiency and decreased accuracy of DSB repair by nonhomologous end joining (NHEJ), which is required for rejoining DSBs during VDJ recombination. Reduced NHEJ repair probably results from reduced expression of Ku86, a key component of the classic DNA-PK-dependent NHEJ pathway. In compensation, early pro-B cells from FLT3/ITD cells mice show increased levels of the alternative, and highly error-prone, NHEJ pathway protein PARP1, explaining the increase in repair errors. These data suggest that, in early pro-B cells from FLT3/ITD mice, impairment of classic NHEJ decreases the ability of cells to complete postcleavage DSB ligation, resulting in failure to complete VDJ recombination and subsequent block of B-lymphocyte maturation. These findings might explain the poor prognosis of leukemia patients with constitutive activation of FLT3 signaling.

scholarly journals Regulation of Energy Metabolism during Early B Lymphocyte Development

2018 ◽  
Vol 19 (8) ◽  
pp. 2192 ◽  
Author(s):  
Sophia Urbanczyk ◽  
Merle Stein ◽  
Wolfgang Schuh ◽  
Hans-Martin Jäck ◽  
Dimitrios Mougiakakos ◽  
...  
Keyword(s):  
B Cells ◽  
Oxidative Phosphorylation ◽  
B Cell ◽  
Metabolic Regulation ◽  
B Lymphocyte ◽  
Cell Development ◽  
B Cell Development ◽  
Disease States ◽  
Receptor Repertoire ◽  
Regulation Of Glycolysis

The most important feature of humoral immunity is the adaptation of the diversity of newly generated B cell receptors, that is, the antigen receptor repertoire, to the body’s own and foreign structures. This includes the transient propagation of B progenitor cells and B cells, which possess receptors that are positively selected via anabolic signalling pathways under highly competitive conditions. The metabolic regulation of early B-cell development thus has important consequences for the expansion of normal or malignant pre-B cell clones. In addition, cellular senescence programs based on the expression of B cell identity factors, such as Pax5, act to prevent excessive proliferation and cellular deviation. Here, we review the basic mechanisms underlying the regulation of glycolysis and oxidative phosphorylation during early B cell development in bone marrow. We focus on the regulation of glycolysis and mitochondrial oxidative phosphorylation at the transition from non-transformed pro- to pre-B cells and discuss some ongoing issues. We introduce Swiprosin-2/EFhd1 as a potential regulator of glycolysis in pro-B cells that has also been linked to Ca2+-mediated mitoflashes. Mitoflashes are bioenergetic mitochondrial events that control mitochondrial metabolism and signalling in both healthy and disease states. We discuss how Ca2+ fluctuations in pro- and pre-B cells may translate into mitoflashes in early B cells and speculate about the consequences of these changes.

scholarly journals Rho GTPase Cdc42 is essential for B-lymphocyte development and activation

Blood ◽  
2009 ◽  
Vol 114 (14) ◽  
pp. 2909-2916 ◽  
Author(s):  
Fukun Guo ◽  
Chinavenmeni S. Velu ◽  
H. Leighton Grimes ◽  
Yi Zheng
Keyword(s):  
B Cells ◽  
B Cell ◽  
B Lymphocyte ◽  
Rho Gtpase ◽  
Cell Development ◽  
B Cell Development ◽  
Immunoglobulin M ◽  
Cell Populations ◽  
Hematopoietic Stem ◽  
Cell Functions

Cdc42 is a member of the Rho GTPase family that has been implicated in several cell functions including proliferation and migration, but its physiologic role needs to be dissected in each cell type. We achieved B-cell and hematopoietic stem cell deletion of Cdc42 by conditional gene targeting in mice. Deletion of Cdc42 from proB/preB-cell stage significantly blocked B-cell development at T1 and later stages, resulting in reduced mature B-cell populations and reduced antigen-specific immunoglobulin M (IgM), IgG1, and IgG3 production. The Cdc42−/− B cells, themselves, were abnormal with impaired proliferation and survival. The mutant B cells were further characterized by a B-cell receptor (BCR) signaling defect with increased Erk and decreased Akt activation, as well as a defect in BCR-mediated B-cell–activating factor (BAFF) receptor up-regulation and subsequent BAFF receptor signaling in mature resting B cells. Surprisingly, Cdc42 was dispensable for stromal cell–derived factor-1α (SDF-1α)– or B-lymphocyte chemoattractant (BLC)–induced B-cell migration. Finally, loss of Cdc42 from hematopoietic stem cells did not alter common lymphoid progenitor production but severely reduced proB/preB- and immature B-cell populations, indicating that Cdc42 is also involved in B-cell precursor differentiation. These results reveal multifaceted roles of Cdc42 in B-cell development and activation.

scholarly journals The endoplasmic reticulum–resident E3 ubiquitin ligase Hrd1 controls a critical checkpoint in B cell development in mice

2018 ◽  
Vol 293 (33) ◽  
pp. 12934-12944 ◽  
Author(s):  
Yi Yang ◽  
Sinyi Kong ◽  
Yana Zhang ◽  
Johanna Melo-Cardenas ◽  
Beixue Gao ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
B Cell ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Cell Development ◽  
B Cell Development

scholarly journals The B Lymphocyte-Specific Coactivator BOB.1/OBF.1 Is Required at Multiple Stages of B-Cell Development

2001 ◽  
Vol 21 (5) ◽  
pp. 1531-1539 ◽  
Author(s):  
Jochen Hess ◽  
Peter J. Nielsen ◽  
Klaus-Dieter Fischer ◽  
Hermann Bujard ◽  
Thomas Wirth
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
B Lymphocyte ◽  
Bone Marrow Cells ◽  
Expression System ◽  
Cell Development ◽  
B Cell Development ◽  
B Cell Differentiation ◽  
Conditional Expression

ABSTRACT The transcriptional coactivator BOB.1/OBF.1 confers B-cell specificity on the transcription factors Oct1 and Oct2 at octamer site-containing promoters. A hallmark of the BOB.1/OBF.1 mutation in the mouse is the absence of germinal center development in secondary lymphoid organs, demonstrating the requirement for BOB.1/OBF.1 in antigen-dependent stages of B-cell differentiation. Here we analyzed earlier stages of B lymphopoiesis in BOB.1/OBF.1-deficient mice. Examination of B-cell development in the bone marrow revealed that the numbers of transitional immature (B220+ IgMhi) B cells were reduced and that B-cell apoptosis was increased. When in competition with wild-type cells, BOB.1/OBF.1−/− bone marrow cells exhibited defects in repopulating the bone marrow B-cell compartment and were unable to establish a presence in the periphery of host mice. The defective bone marrow populations in BOB.1/OBF.1−/− mice were rescued by conditional expression of a BOB.1/OBF.1 transgene controlled by the tetracycline gene expression system. However, the restored populations did not restore the numbers of IgDhi B cells in the periphery, where the BOB.1/OBF.1 transgene was not expressed. These results show that BOB.1/OBF.1−/− B cells exhibit multistage defects in B-cell development, including impaired production of transitional B cells and defective maturation of recirculating B cells.

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