Abstract
B lymphocyte stimulator (BLyS), a TNF family protein essential for peripheral B cell development, functions primarily through attenuation of B cell apoptosis. In this study, we show that BLyS activates NF-kappaB through both classical and alternative pathways with distinct kinetics in quiescent mature B cells. It rapidly and transiently enhances the p50/p65 DNA binding activity and induces phosphorylation of IkappaBalpha characteristic of the classical NF-kappaB pathway, albeit maintaining IkappaBalpha at a constant level through ongoing protein synthesis and proteasome-mediated destruction. With delayed kinetics, BLyS promotes the processing of p100 to p52 and sustained formation of p52/RelB complexes via the alternative NF-kappaB pathway. p50 is dispensable for p100 processing. However, it is required to mediate the initial BLyS survival signals and concomitant activation of Bcl-x(L) in quiescent mature B cells ex vivo. Although also a target of BLyS activation, at least one of the A1 genes, A1-a, is dispensable for the BLyS survival function. These results suggest that BLyS mediates its survival signals in metabolically restricted quiescent B cells, at least in part, through coordinated activation of both NF-kappaB pathways and selective downstream antiapoptotic genes.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / genetics
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Apoptosis / immunology*
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B-Cell Activating Factor
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B-Lymphocyte Subsets / cytology
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B-Lymphocyte Subsets / metabolism*
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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Cell Survival / genetics
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Cell Survival / immunology
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I-kappa B Proteins / metabolism
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Interphase / genetics
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Interphase / immunology*
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Membrane Proteins / physiology*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Minor Histocompatibility Antigens
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NF-KappaB Inhibitor alpha
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / deficiency
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NF-kappa B / genetics
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NF-kappa B / metabolism*
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NF-kappa B / physiology*
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NF-kappa B p50 Subunit
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NF-kappa B p52 Subunit
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Phosphorylation
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Protein Biosynthesis
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Protein Processing, Post-Translational / genetics
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Protein Processing, Post-Translational / immunology*
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Proto-Oncogene Proteins c-bcl-2 / deficiency
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Signal Transduction / genetics
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Signal Transduction / immunology
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Transcription Factor RelA
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Tumor Necrosis Factor-alpha / physiology*
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Up-Regulation / genetics
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Up-Regulation / immunology
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bcl-X Protein
Substances
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B-Cell Activating Factor
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BCL2-related protein A1
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Bcl2l1 protein, mouse
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I-kappa B Proteins
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Membrane Proteins
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Minor Histocompatibility Antigens
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NF-kappa B
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NF-kappa B p50 Subunit
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NF-kappa B p52 Subunit
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Nfkbia protein, mouse
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Proto-Oncogene Proteins c-bcl-2
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Tnfsf13b protein, mouse
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Transcription Factor RelA
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Tumor Necrosis Factor-alpha
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bcl-X Protein
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NF-KappaB Inhibitor alpha