Identification of proteoglycans as the APRIL-specific binding partners - PubMed (original) (raw)
Comparative Study
. 2005 May 2;201(9):1375-83.
doi: 10.1084/jem.20042309. Epub 2005 Apr 25.
Adrian Zumsteg, Aubry Tardivel, Bertrand Huard, Quynh-Giao Steiner, Teresa G Cachero, Fang Qiang, Leonid Gorelik, Susan L Kalled, Hans Acha-Orbea, Paul D Rennert, Jürg Tschopp, Pascal Schneider
Affiliations
- PMID: 15851487
- PMCID: PMC2213192
- DOI: 10.1084/jem.20042309
Comparative Study
Identification of proteoglycans as the APRIL-specific binding partners
Karine Ingold et al. J Exp Med. 2005.
Abstract
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.
Figures
Figure 1.
The NH2 terminus of mature APRIL is required for interaction with HEK-293T cells, but not with BCMA and TACI. (A) The sequence of APRIL and BAFF is depicted around the mature NH2 terminus. The box outlines the furin recognition sequence. The open arrow points to the cleavage site. The bold letters depict basic amino acids. The line on top of the alignment indicates the start of the TNF homology domain. The asterisk represents the 32–amino acid sequence insertion in murine BAFF. (B) 293T cells cotransfected with the indicated receptors, plus an EGFP tracer, were stained with Fc:BAFF, Fc:APRIL H98, or Fc:APRIL A88. Pentameric BCMA:COMP-Flag (soluble BCMA) and heparin were used as competitors, either alone or in combination. Both axes show fluorescent intensity on a logarithmic scale (100–104). The small residual binding of BAFF to BCMA in the presence of soluble BCMA, but not in the presence of BCMA plus heparin, does not reflect a specific effect of heparin on BAFF binding, but rather an experimental variation. This was not observed in three other independent experiments.
Figure 2.
The NH2 terminus of mature APRIL and other basic residues are required for heparin binding. (A) Flag-tagged ligands were immunoprecipitated with either BCMA:Fc or heparin-Sepharose. Naturally processed, untagged APRIL was also used. Proteins were detected by immunoblot with anti-Flag or anti-APRIL mAbs as indicated. (B) Schematic representation of the constructs used in A. (C) Structure of the APRIL–BCMA complex (reference 10), showing one subunit of the trimer. Side chains of all basic amino acid residues that are present on the upper surface of APRIL are shown (gray, common to APRIL and BAFF; black, APRIL specific [R129, R172, and H203]). The basic NH2 terminus of mature APRIL, which is only partially apparent in the crystal structure, comprises K97. A heparin fragment is shown above its proposed binding site. APRIL, BCMA, and heparin were drawn using the PDB atomic coordinate files 1XU2 and 1FQ9.
Figure 3.
APRIL binds the sulfated glycosaminoglycan side chains of proteoglycans. (A) 293T cells grown in the presence or absence of the sulfation inhibitor chlorate were stained with Fc versions of the indicated human (h) or murine (m) APRILs. (B) Jurkat cells cotransfected with various human syndecan or glypican expression constructs and an EGFP tracer were stained with Fc versions of human BAFF, APRIL H98, or APRIL A88. Both axes show fluorescent intensity on a logarithmic scale (100–104).
Figure 4.
APRIL binding to primary syndecan-1–positive plasma cells. (A) Flow cytometry analysis of draining popliteal lymph nodes from mouse mammary tumor virus–infected mouse. B220 and CD138 stainings were used to define B cell (B), plasma cell (PC), and T cell and other cell (T) populations as indicated. (B) Staining of cell populations defined in A with Fc versions of mouse BAFF or APRIL A88, in the presence or absence of heparin.
Figure 5.
Antibody-mediated cross-linking of APRIL potentiates B cell costimulation. (A) Purified splenic mouse B cells were stimulated with anti-IgM antibodies and costimulated for 3 d with the indicated Flag-tagged murine ligands, in the presence or absence of anti-Flag antibody or heparin. Proliferation was monitored by thymidine incorporation. (B) B cells purified from spleen, lymph nodes, and blood where stimulated as in A with the indicated Flag-tagged ligands in the presence of anti-Flag antibody.
Figure 6.
BAFF and APRIL are important for the migration or survival of newly formed plasma cells to the bone marrow. 6 d after immunization with NP21–CGG, mice were treated with normal IgG, BCMA:Fc, or BAFFR:Fc. 5 d after treatment, ELISPOT assays were used to determine the frequencies of specific plasma cells (A) in the spleen and (B) in the bone marrow. (C) Titers of specific IgG1 in sera were determined by ELISA and normalized against the value obtained for a 1:50,000 dilution of hyperimmunized mouse serum. Results from two representative experiments with a total number of 8–10 mice in each treatment group are shown. The experiment using four to five mice per group was repeated four times with similar results. P-values are indicated above the groups when significantly different (P < 0.05) from the control-treated animals.
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