Discrete roles and bifurcation of PTEN signaling and mTORC1-mediated anabolic metabolism underlie IL-7–driven B lymphopoiesis

Yu, Mei; Tan, Haidong; Li, Yuxin; Su, Wei; Shi, Hao; Dhungana, Yogesh; Guy, Cliff; Neale, Geoffrey; Cloer, Caryn; Peng, Junmin; Wang, Demin; Chi, Hongbo

doi:10.1126/sciadv.aar5701

Cited by 37 publications

(67 citation statements)

References 102 publications

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“…Extracellular flux analyses performed with sorted primary pro- and pre-B cells obtained from this system revealed that in general, under normoxic conditions, OCR and ECAR were lower in Rag1 −/− ;33.C9μHCki pre-B cells than pro-B cells. These data were confirmed by Zeng et al, who also analysed immature B cells, which have an OCR similar to that of small pre-B cells [22]. In contrast to Zeng et al we also assessed glycolysis.…”

Section: Oxidative Phosphorylation and Glycolysis In Pro- And Pre-supporting

confidence: 70%

Regulation of Energy Metabolism during Early B Lymphocyte Development

Urbanczyk

Stein

Schuh

et al. 2018

IJMS

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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.

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Section: Oxidative Phosphorylation and Glycolysis In Pro- And Pre-supporting

confidence: 70%

Regulation of Energy Metabolism during Early B Lymphocyte Development

Urbanczyk

Stein

Schuh

et al. 2018

IJMS

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“…Within the immune system mTORC1 coordinates signals via the T cell receptor and the IL-2 receptor to solidify regulatory T cell function through the eventual upregulation of T cell-affiliated surface receptors that confer immune suppression 52 . Within the B cell lineage recent work suggests that mTORC1 facilitates metabolic reprograming needed for B cell progenitors to proliferate in response to IL-7 53 , while also optimizing several important aspects of germinal center B cell differentiation including Bcl6 expression 54,55 . Our studies reveal additional insights into cell-type and context-specific mTORC1 functions.…”

Section: Discussionmentioning

confidence: 99%

mTORC1 coordinates an immediate unfolded protein response-related transcriptome in activated B cells preceding antibody secretion

et al. 2020

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How activated B cells build biosynthetic pathways and organelle structures necessary for subsequent robust antibody secretion is still unclear. The dominant model holds that nascent plasma cells adapt to increased antibody synthesis by activating the unfolded protein response (UPR) under the control of the transcription factor Xbp1. Here, by analyzing gene expression in activated B cells with or without plasma cell-inductive signals, we find that follicular B cells up-regulate a wide array of UPR-affiliated genes before initiating antibody secretion; furthermore, initial transcription of these loci requires the mTORC1 kinase adaptor, Raptor, but not Xbp1. Transcriptomic analyses of resting marginal zone B cells, which generate plasma cells with exceptionally rapid kinetics, reinforce these results by revealing the basal expression of UPR-affiliated mRNA networks without detectable Xbp1 activity. We thus conclude that B cells utilize mTORC1 to prepare for subsequent plasma cell function, before the onset of antibody synthesis.

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“…13 Consistent with their different rates of proliferation, pro-B cells, large and small pre-B cells, and immature B cells differ significantly in their metabolic profile. 14,15 To foster cell growth, IL-7 induces activation of signaling molecules such as mechanistic target of rapamycin complex 1 (mTORC1) and c-Myc, which drive an anabolic metabolic program 15,16 indispensable for B cell development ( Figure 1). Both mTORC1 and c-Myc are known metabolic master regulators, which are activated in response to mitogenic signals.…”

Section: Me Taboli C Bal An Ce In B Cell Precur Sor Smentioning

confidence: 99%

“…Consistently, the deletion of the negative PI3K regulator phosphatase and tensin homolog (PTEN) inhibits normal B cell development. 15,31 However, constitutively active Foxo1 cannot rescue B cell development in PTEN-deficient mice suggesting that PI3K signaling also plays Foxo1-independent roles in B cell precursors. 15 Recent studies demonstrate that Pten deletion compromises BCR-Abl1-or NRAS-driven leukemogenesis 32 (Figure 2).…”

Section: Pre-b Cells Have Been Shown To Lose Viability Upon the Deletmentioning

confidence: 99%

“…15,31 However, constitutively active Foxo1 cannot rescue B cell development in PTEN-deficient mice suggesting that PI3K signaling also plays Foxo1-independent roles in B cell precursors. 15 Recent studies demonstrate that Pten deletion compromises BCR-Abl1-or NRAS-driven leukemogenesis 32 (Figure 2). Upon PTEN loss, B cell acute lymphoblastic leukemia (B-ALL) cells show increased glucose consumption and lactate production but decreased ATP levels.…”

Section: Pre-b Cells Have Been Shown To Lose Viability Upon the Deletmentioning

confidence: 99%

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The role of metabolic checkpoint regulators in B cell survival and transformation

Jellusova

2020

Immunological Reviews

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In response to mitogenic stimulation, B cells activate different pro-anabolic signaling pathways such as c-Myc-and mTORC1-dependent networks to satisfy the energetic demands of biomass synthesis and proliferation. In order to preserve viability and function, cell growth cannot progress unchecked and must be adjusted according to the availability of nutrients. Nutrient-sensing proteins such as AMPK antagonize mTORC1 activity in response to starvation. If pro-anabolic signaling pathways are aberrantly activated, B cells may lack the metabolic capacity to accommodate their energetic needs, which can lead to cell death. On the other hand, metabolic hyperactivation is a salient feature of cancer cells, suggesting that mechanisms exist, which allow B cells to cope with metabolic stress. The aim of this review is to discuss how B cells respond to a mismatch between energy supply and demand and what the consequences are of metabolic dysregulation in normal and malignant B cells. K E Y W O R D Sanabolism, autophagy, B cells, metabolic stress, mTORC1, senescence

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Discrete roles and bifurcation of PTEN signaling and mTORC1-mediated anabolic metabolism underlie IL-7–driven B lymphopoiesis

Abstract: PTEN-PI3K and IL-7R–mTORC1–Myc are two discrete signaling axes driving B cell development.

Cited by 37 publications

References 102 publications

Regulation of Energy Metabolism during Early B Lymphocyte Development

Regulation of Energy Metabolism during Early B Lymphocyte Development

mTORC1 coordinates an immediate unfolded protein response-related transcriptome in activated B cells preceding antibody secretion

The role of metabolic checkpoint regulators in B cell survival and transformation

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