BCR-Induced Ca2+ Signals Dynamically Tune Survival, Metabolic Reprogramming, and Proliferation of Naive B Cells
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 var...
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| Vydané v: | Cell reports (Cambridge) Ročník 31; číslo 2; s. 107474 |
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| Hlavní autori: | , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | English |
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14.04.2020
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| ISSN: | 2211-1247, 2211-1247 |
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| 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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| AbstractList | 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.
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. 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. [Display omitted] •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. 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.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. |
| ArticleNumber | 107474 |
| Author | Liu, Xiaohong Berry, Corbett T. May, Michael J. Hershberg, Uri Lengner, Christopher J. Freedman, Bruce D. Cancro, Michael P. Chen, Youhai H. Myles, Arpita Nandi, Satabdi Brodsky, Igor E. |
| AuthorAffiliation | 2 School of Biomedical Engineering, Science and Health Systems, Drexel University, PA 19104, USA 3 Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA 5 University of Pennsylvania Institute for Regenerative Medicine, Philadelphia, PA 19104, USA 7 Lead Contact 6 Department of Human Biology, Faculty of Sciences, University of Haifa, Haifa 3498838, Israel 4 Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA 1 Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA |
| AuthorAffiliation_xml | – name: 5 University of Pennsylvania Institute for Regenerative Medicine, Philadelphia, PA 19104, USA – name: 7 Lead Contact – name: 3 Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA – name: 6 Department of Human Biology, Faculty of Sciences, University of Haifa, Haifa 3498838, Israel – name: 4 Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA – name: 2 School of Biomedical Engineering, Science and Health Systems, Drexel University, PA 19104, USA – name: 1 Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA |
| Author_xml | – sequence: 1 givenname: Corbett T. surname: Berry fullname: Berry, Corbett T. organization: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA – sequence: 2 givenname: Xiaohong surname: Liu fullname: Liu, Xiaohong organization: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA – sequence: 3 givenname: Arpita surname: Myles fullname: Myles, Arpita organization: Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA – sequence: 4 givenname: Satabdi surname: Nandi fullname: Nandi, Satabdi organization: Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA – sequence: 5 givenname: Youhai H. surname: Chen fullname: Chen, Youhai H. organization: Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA – sequence: 6 givenname: Uri surname: Hershberg fullname: Hershberg, Uri organization: School of Biomedical Engineering, Science and Health Systems, Drexel University, PA 19104, USA – sequence: 7 givenname: Igor E. surname: Brodsky fullname: Brodsky, Igor E. organization: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA – sequence: 8 givenname: Michael P. surname: Cancro fullname: Cancro, Michael P. organization: Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA – sequence: 9 givenname: Christopher J. surname: Lengner fullname: Lengner, Christopher J. organization: Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA – sequence: 10 givenname: Michael J. surname: May fullname: May, Michael J. organization: Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA – sequence: 11 givenname: Bruce D. orcidid: 0000-0003-4487-7210 surname: Freedman fullname: Freedman, Bruce D. email: bruce@vet.upenn.edu organization: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA |
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| Keywords | CD40 Bcl-xL STIM1 c-Myc nuclear factor kappa B c-Rel Orai1 apoptosis mTORC1 NFAT |
| Language | English |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 AUTHOR CONTRIBUTIONS Conceptualization, C.T.B. and B.D.F.; Methodology, C.T.B. and B.D.F.; Investigation, C.T.B., X.L., A.M., S.N., and B.D.F.; Writing – Original Draft, C.T.B., M.J.M., and B.D.F.; Writing – Review & Editing, C.T.B, Y.H.C., I.E.B., M.P.C., C.J.L., and B.D.F.; Funding Acquisition, B.D.F. and M.J.M.; Resources, B.D.F., Y.H.C., I.E.B., M.P.C., C.J.L., and M.J.M.; Supervision, B.D.F. |
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