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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Vydáno v:	Cell reports (Cambridge) Ročník 31; číslo 2; s. 107474
Hlavní autoři:	Berry, Corbett T., Liu, Xiaohong, Myles, Arpita, Nandi, Satabdi, Chen, Youhai H., Hershberg, Uri, Brodsky, Igor E., Cancro, Michael P., Lengner, Christopher J., May, Michael J., Freedman, Bruce D.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	Elsevier Inc 14.04.2020
Témata:	apoptosis Bcl-xL c-Myc c-Rel CD40 mTORC1 NFAT nuclear factor kappa B Orai1 STIM1 CD40 Bcl-xL STIM1 c-Myc nuclear factor kappa B c-Rel Orai1 apoptosis mTORC1 NFAT
ISSN:	2211-1247, 2211-1247
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Shrnutí:	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.
Bibliografie:	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.
ISSN:	2211-1247 2211-1247
DOI:	10.1016/j.celrep.2020.03.038