Abstract
The TNF-like ligand BAFF/BLyS is a potent survival factor for B cells. It binds three receptors: TACI, BCMA, and BR3. We show that BR3 signaling promotes processing of the transcription factor NF-kappaB2/p100 to p52. NF-kappaB2/p100 cleavage was abrogated in B cells from A/WySnJ mice possessing a mutant BR3 gene, but not in TACI or BCMA null B cells. Furthermore, wild-type mice injected with BAFF-neutralizing BR3-Fc protein showed reduced basal NF-kappaB2 activation. BR3-Fc treatment of NZB/WF1 mice, which develop a fatal lupus-like syndrome, inhibited NF-kappaB2 processing and attenuated the disease process. Since inhibiting the BR3-BAFF interaction has therapeutic ramifications, the ligand binding interface of BR3 was investigated and found to reside within a 26 residue core domain. When stabilized within a structured beta-hairpin peptide, six of these residues were sufficient to confer binding to BAFF.
MeSH terms
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Amino Acid Sequence
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Animals
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Apoptosis
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B-Cell Activating Factor
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B-Cell Activation Factor Receptor
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B-Lymphocytes / cytology
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B-Lymphocytes / immunology*
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B-Lymphocytes / metabolism*
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Binding Sites
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Cell Line
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Female
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Ligands
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Lupus Erythematosus, Systemic / immunology
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Membrane Proteins / metabolism*
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Mice
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Mice, Inbred A
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Mice, Inbred C57BL
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Mice, Inbred NZB
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Mice, Knockout
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Mice, Mutant Strains
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Models, Molecular
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Molecular Sequence Data
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NF-kappa B / metabolism*
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NF-kappa B p52 Subunit
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Protein Processing, Post-Translational
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Protein Structure, Tertiary
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Receptors, Tumor Necrosis Factor / chemistry
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Receptors, Tumor Necrosis Factor / genetics
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Receptors, Tumor Necrosis Factor / metabolism*
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Signal Transduction
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Tumor Necrosis Factor-alpha / metabolism*
Substances
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B-Cell Activating Factor
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B-Cell Activation Factor Receptor
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Ligands
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Membrane Proteins
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NF-kappa B
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NF-kappa B p52 Subunit
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Receptors, Tumor Necrosis Factor
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Tnfrsf13c protein, mouse
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Tnfsf13b protein, mouse
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Tumor Necrosis Factor-alpha