Identification of proteoglycans as the APRIL-specific binding partners.
B cell activating factor of the tumor necrosis factor (TNF) family (BAFF) and a proliferation-inducing ligand (APRIL) are closely related ligands within the TNF superfamily that play important roles in B lymphocyte biology. Both ligands share two receptors--transmembrane activator and calcium signal--modulating cyclophilin ligand interactor (TACI) and B cell maturation antigen (BCMA)--that are predominantly expressed on B cells. In addition, BAFF specifically binds BAFF receptor, whereas the nature of a postulated APRIL-specific receptor remains elusive. We show that the TNF homology domain of APRIL binds BCMA and TACI, whereas a basic amino acid sequence (QKQKKQ) close to the NH2 terminus of the mature protein is required for binding to the APRIL-specific "receptor." This interactor was identified as negatively charged sulfated glycosaminoglycan side chains of proteoglycans. Although T cell lines bound little APRIL, the ectopic expression of glycosaminoglycan-rich syndecans or glypicans conferred on these cells a high binding capacity that was completely dependent on APRIL's basic sequence. Moreover, syndecan-1-positive plasma cells and proteoglycan-rich nonhematopoietic cells displayed high specific, heparin-sensitive binding to APRIL. Inhibition of BAFF and APRIL, but not BAFF alone, prevented the survival and/or the migration of newly formed plasma cells to the bone marrow. In addition, costimulation of B cell proliferation by APRIL was only effective upon APRIL oligomerization. Therefore, we propose a model whereby APRIL binding to the extracellular matrix or to proteoglycan-positive cells induces APRIL oligomerization, which is the prerequisite for the triggering of TACI- and/or BCMA-mediated activation, migration, or survival signals.
Ingold
Karine
K
Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland.
Zumsteg
Adrian
A
Tardivel
Aubry
A
Huard
Bertrand
B
Steiner
Quynh-Giao
QG
Cachero
Teresa G
TG
Qiang
Fang
F
Gorelik
Leonid
L
Kalled
Susan L
SL
Acha-Orbea
Hans
H
Rennert
Paul D
PD
Tschopp
Jürg
J
Schneider
Pascal
P
D000818:Animals; D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D053301:B-Cell Maturation Antigen; D001402:B-Lymphocytes / Q000378:metabolism*; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D005434:Flow Cytometry; D006493:Heparin / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism*; D010950:Plasma Cells / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011509:Proteoglycans / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D014162:Transfection; D053303:Transmembrane Activator and CAML Interactor Protein; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C490341:ANP32B protein, human; D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D053301:B-Cell Maturation Antigen; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011509:Proteoglycans; D018124:Receptors, Tumor Necrosis Factor; C108467:TNFRSF13B protein, human; C435926:TNFRSF13C protein, human; C086966:TNFRSF17 protein, human; C505719:TNFSF13B protein, human; C505720:Tnfsf13b protein, mouse; D053303:Transmembrane Activator and CAML Interactor Protein; D014409:Tumor Necrosis Factor-alpha; D006493:Heparin