RESUMEN
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.
Asunto(s)
Proteoglicanos de Heparán Sulfato/metabolismo , Proteínas de la Membrana/metabolismo , Neoplasias/metabolismo , Neoplasias/patología , Factor de Necrosis Tumoral alfa/metabolismo , Secuencia de Aminoácidos , Animales , Línea Celular , Proliferación Celular , Chlorocebus aethiops , Humanos , Linfocitos/citología , Linfocitos/metabolismo , Proteínas de la Membrana/química , Proteínas de la Membrana/genética , Ratones , Datos de Secuencia Molecular , Mutación/genética , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral , Factor de Necrosis Tumoral alfa/química , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
The tumour necrosis factor (TNF) family is intimately connected to the regulation of cellular pathways. A PRoliferation-Inducing Ligand (APRIL) is a rather new member of that family, named for its capacity to stimulate the proliferation of tumour cells in vitro. Subsequent publications also called this ligand TRDL-1 or TALL-2, respectively. APRIL and B-lymphocyte stimulator (BLyS; also termed BAFF, TALL-1, THANK, zTNF4) form a new subfamily of TNF-like ligands that are expressed in haematopoietic cells. Both ligands can bind the two members of the TNF receptor family, namely the transmembrane activator and calcium modulator cyclophilin ligand interactor (TACI), as well as B-cell maturation antigen (BCMA). BLyS has recently been the subject of several reviews (for an extensive review, see Mackay et al.). The present review will thus focus on APRIL, and discuss BLyS only briefly for the sake of clarity.