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Journal article
BCR-Induced Ca2+ Signals Dynamically Tune Survival, Metabolic Reprogramming, and Proliferation of Naive B Cells
Cell reports (Cambridge), v 31(2), 107474
14 Apr 2020
PMID: 32294437
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
B cell receptor (BCR) engagement induces naive B cells to differentiate and perform critical immune-regulatory functions. Acquisition of functional specificity requires that a cell survive, enter the cell cycle, and proliferate. We establish that quantitatively distinct Ca2+ signals triggered by variations in the extent of BCR engagement dynamically regulate these transitions by controlling nuclear factor κB (NF-κB), NFAT, and mTORC1 activity. Weak BCR engagement induces apoptosis by failing to activate NF-κB-driven anti-apoptotic gene expression. Stronger signals that trigger more robust Ca2+ signals promote NF-κB-dependent survival and NFAT-, mTORC1-, and c-Myc-dependent cell-cycle entry and proliferation. Finally, we establish that CD40 or TLR9 costimulation circumvents these Ca2+-regulated checkpoints of B cell activation and proliferation. As altered BCR signaling is linked to autoimmunity and B cell malignancies, these results have important implications for understanding the pathogenesis of aberrant B cell activation and differentiation and therapeutic approaches to target these responses.
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•BCR signal strength is encoded as quantitatively distinct intracellular Ca2+ signals•Ca2+ dynamics are decoded by NF-κB, NFAT, and mTORC1 to drive cell fates•BCR-induced Ca2+ signals are required for maximal B cell survival and proliferation•CD40 compensates for weak BCR/Ca2+ signals to rescue NF-κB- and mTORC1-dependent fates
Berry et al. establish that variations in the strength of BCR engagement are encoded as quantitatively distinct calcium signals that tune B cell fates by dynamically regulating NF-κB, NFAT, and mTORC1 activity. Targeting calcium signaling may thereby serve as an effective treatment strategy for regulating normal and pathological B cell activation.
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Details
- Title
- BCR-Induced Ca2+ Signals Dynamically Tune Survival, Metabolic Reprogramming, and Proliferation of Naive B Cells
- Creators
- Corbett T. Berry - Drexel UniversityXiaohong Liu - University of PennsylvaniaArpita Myles - University of PennsylvaniaSatabdi Nandi - University of PennsylvaniaYouhai H. Chen - University of PennsylvaniaUri Hershberg - University of HaifaIgor E. Brodsky - University of PennsylvaniaMichael P. Cancro - University of PennsylvaniaChristopher J. Lengner - California Institute for Regenerative MedicineMichael J. May - University of PennsylvaniaBruce D. Freedman - University of Pennsylvania
- Publication Details
- Cell reports (Cambridge), v 31(2), 107474
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems
- Web of Science ID
- WOS:000526938500004
- Scopus ID
- 2-s2.0-85083165082
- Other Identifier
- 991019167546204721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Cell Biology