The Journal of Experimental Medicine
BioLegend: PerCP, PerCP/Cy5.5 Ab Conjugates
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Published online 25 April 2005 doi:10.1084/jem.20042309
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 9, 1375-1383
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ARTICLE

 Identification of proteoglycans as the APRIL-specific binding partners

Karine Ingold1, Adrian Zumsteg1, Aubry Tardivel1, Bertrand Huard2, Quynh-Giao Steiner1, Teresa G. Cachero3, Fang Qiang3, Leonid Gorelik3, Susan L. Kalled3, Hans Acha-Orbea1, Paul D. Rennert3, Jürg Tschopp1, and Pascal Schneider1

1 Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland
2 Department of Dermatology, University of Geneva Medical Center, CH-1211 Geneva 4, Switzerland
3 Biogen Idec, Cambridge, MA 02142

CORRESPONDENCE Pascal Schneider: pascal.schneider{at}unil.ch

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.

Abbreviations used: APRIL, a proliferation-inducing ligand; BAFF, B cell activating factor of the TNF family; BAFF-R, BAFF receptor; BCMA, B cell maturation antigen; COMP, cartilage matrix oligomeric protein; EDA, ectodysplasin A; TACI, transmembrane activator and calcium signal–modulating cyclophilin ligand interactor.

A. Zumsteg's present address is Institute for Biochemistry and Genetics, University of Basel, CH-4058 Basel, Switzerland.


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