Identification of proteoglycans as the APRIL-specific binding partners

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.

Intrarenal production of B-cell survival factors in human lupus nephritis

“…42,43 Mesangial cell-derived APRIL may promote survival and proliferation in an autocrine or paracrine, e.g., proteoglycan-receptor-mediated, manner leading to increased glomerular cellularity. 6,44,45 On the other hand, the expression of BLyS and BAFF-R in inflammatory cells of the interstitium in lupus nephritis, as described by us, may help sustain autocrine B 31 and T lymphocytemediated inflammation in the tubulointerstitial compartment of kidneys with lupus nephritis. In the glomerular compartment, few T cells, even fewer B cells and no dendritic cells are typically present.…”

“…4 APRIL may also bind to heparan sulfate proteoglycans. 6,7 The receptors for BAFF and APRIL are mainly expressed on B cells. 4 In addition to the well established role in B-cell survival, these factors exert functions on different subsets of cells, eg, T cells 4,5 and monocytes.…”

Rare mutations in TNFRSF13B increase the risk of asthma symptoms in Swedish children

“…22 Signaling through TACI requires a trimerization of the receptor. [23][24][25] It is thus possible that inclusion of even one mutant receptor might affect the signaling by the complex. This might suggest a route of action for the R202H mutation, which is situated in the intracellular part of the protein.…”

Heparan sulphate proteoglycans are essential for the myeloma cell growth activity of EGF-family ligands in multiple myeloma

“…Whether our present data can be extended to other myeloma growth factors is under active investigation in the laboratory. Two recent studies demonstrated that APRIL, a growth factor for myeloma cells (Moreaux et al, 2004), can bind HSPG (Hendriks et al, 2005;Ingold et al, 2005). One study reported that IL-6, the major known MMC growth factor (Klein et al, 1989), is a heparin-binding cytokine and that a heparin mimetic inhibits the biological activity of IL-6 and the binding to its receptors (Mummery and Rider, 2000).…”