APRIL, a proliferation-inducing
ligand, is a member of the
tumor necrosis factor (TNF) family that is expressed by various types of
tumors and influences their growth in vitro and in vivo. Two receptors, transmembrane activator and
cyclophilin ligand interactor (TACI) and
B-cell maturation antigen (
BCMA), bind APRIL, but neither is essential for the
tumor-promoting effects, suggesting that a third receptor exists. Here, we report that APRIL specifically binds to
heparan sulfate proteoglycans (
HSPG) on the surface of
tumor cells. This binding is mediated by the
heparin sulfate side chains and can be inhibited by
heparin. Importantly,
BCMA and
HSPG do not compete, but can bind APRIL simultaneously, suggesting that different regions in APRIL are critical for either interaction. In agreement, mutation of three lysines in a putative
heparin sulfate-binding motif, which is not part of the TNF fold, destroys interaction with
HSPG, while binding to
BCMA is unaffected. Finally, whereas interaction of APRIL with
HSPG does not influence APRIL-induced proliferation of T cells, it is crucial for its
tumor growth-promoting activities. We therefore conclude that either
HSPG serve as a receptor for APRIL or that
HSPG binding allows APRIL to interact with a receptor that promotes
tumor growth.