BAFF/BLyS receptor 3 binds the B cell survival factor BAFF ligand through a discrete surface loop and promotes processing of NF-kappaB2.
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.
Kayagaki
Nobuhiko
N
Department of Molecular Oncology, Genentech, Inc., South San Francisco, CA 94080, USA.
Yan
Minhong
M
Seshasayee
Dhaya
D
Wang
Hua
H
Lee
Wyne
W
French
Dorothy M
DM
Grewal
Iqbal S
IS
Cochran
Andrea G
AG
Gordon
Nathaniel C
NC
Yin
JianPing
J
Starovasnik
Melissa A
MA
Dixit
Vishva M
VM
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D001665:Binding Sites; D002460:Cell Line; D005260:Female; D008024:Ligands; D008180:Lupus Erythematosus, Systemic / Q000276:immunology; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D008814:Mice, Inbred NZB; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D052003:NF-kappa B p52 Subunit; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D008024:Ligands; D008565:Membrane Proteins; D016328:NF-kappa B; D052003:NF-kappa B p52 Subunit; D018124:Receptors, Tumor Necrosis Factor; C486662:Tnfrsf13c protein, mouse; C505720:Tnfsf13b protein, mouse; D014409:Tumor Necrosis Factor-alpha