BAFF/BLyS receptor 3 binds the B cell survival factor BAFF ligand through a discrete surface loop and promotes processing of NF-kappaB2

• Published in: Immunity (Cambridge, Mass.) Vol. 17; no. 4; pp. 515 - 524
• Main Authors: Kayagaki, Nobuhiko, Yan, Minhong, Seshasayee, Dhaya, Wang, Hua, Lee, Wyne, French, Dorothy M, Grewal, Iqbal S, Cochran, Andrea G, Gordon, Nathaniel C, Yin, JianPing, Starovasnik, Melissa A, Dixit, Vishva M
• Format: Journal Article
• Language: English
• Published: United States 01-10-2002
• Subjects: Amino Acid Sequence; Animals; Apoptosis; B-Cell Activating Factor; B-Cell Activation Factor Receptor; B-Lymphocytes - cytology; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Binding Sites; Cell Line; Female; Ligands; Lupus Erythematosus, Systemic - immunology; Membrane Proteins - metabolism; Mice; Mice, Inbred A; Mice, Inbred C57BL; Mice, Inbred NZB; Mice, Knockout; Mice, Mutant Strains; Models, Molecular; Molecular Sequence Data; NF-kappa B - metabolism; NF-kappa B p52 Subunit; Protein Processing, Post-Translational; Protein Structure, Tertiary; Receptors, Tumor Necrosis Factor - chemistry; Receptors, Tumor Necrosis Factor - genetics; Receptors, Tumor Necrosis Factor - metabolism; Signal Transduction; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 1074-7613

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.