title: Stoichiometry of Heteromeric BAFF and APRIL Cytokines Dictates Their Receptor Binding and Signaling Properties.
abstract: The closely related TNF family ligands B cell activation factor (BAFF) and a proliferation-inducing ligand (APRIL) serve in the generation and maintenance of mature B-lymphocytes. Both BAFF and APRIL assemble as homotrimers that bind and activate several receptors that they partially share. However, heteromers of BAFF and APRIL that occur in patients with autoimmune diseases are incompletely characterized. The N and C termini of adjacent BAFF or APRIL monomers are spatially close and can be linked to create single-chain homo- or hetero-ligands of defined stoichiometry. Similar to APRIL, heteromers consisting of one BAFF and two APRILs (BAA) bind to the receptors B cell maturation antigen (BCMA), transmembrane activator and CAML interactor (TACI) but not to the BAFF receptor (BAFFR). Heteromers consisting of one APRIL and two BAFF (ABB) bind to TACI and BCMA and weakly to BAFFR in accordance with the analysis of the receptor interaction sites in the crystallographic structure of ABB. Receptor binding correlated with activity in reporter cell line assays specific for BAFFR, TACI, or BCMA. Single-chain BAFF (BBB) and to a lesser extent single-chain ABB, but not APRIL or single-chain BAA, rescued BAFFR-dependent B cell maturation in BAFF-deficient mice. In conclusion, BAFF-APRIL heteromers of different stoichiometries have distinct receptor-binding properties and activities. Based on the observation that heteromers are less active than BAFF, we speculate that their physiological role might be to down-regulate BAFF activity.
authors.affiliation: From the Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland.
authors.forename: Sonia
authors.initials: S
authors.lastname: Schuepbach-Mallepell
authors.affiliation: From the Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland.
authors.forename: Dolon
authors.initials: D
authors.lastname: Das
authors.affiliation: From the Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland.
authors.forename: Laure
authors.initials: L
authors.lastname: Willen
authors.affiliation: From the Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland.
authors.forename: Michele
authors.initials: M
authors.lastname: Vigolo
authors.affiliation: From the Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland.
authors.forename: Aubry
authors.initials: A
authors.lastname: Tardivel
authors.affiliation: From the Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland.
authors.forename: Luc
authors.initials: L
authors.lastname: Lebon
authors.affiliation: From the Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland.
authors.forename: Christine
authors.initials: C
authors.lastname: Kowalczyk-Quintas
authors.affiliation: From the Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland.
authors.forename: Josquin
authors.initials: J
authors.lastname: Nys
authors.affiliation: From the Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland.
authors.forename: Cristian
authors.initials: C
authors.lastname: Smulski
authors.affiliation: Biogen, Cambridge, Massachusetts 02142.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Zheng
authors.affiliation: Proteros Biostructures GmbH, D-82152 Planegg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Maskos
authors.affiliation: Proteros Biostructures GmbH, D-82152 Planegg, Germany.
authors.forename: Alfred
authors.initials: A
authors.lastname: Lammens
authors.affiliation: the EMD Serono Research and Development Institute, Billerica, Massachusetts 01821.
authors.forename: Xuliang
authors.initials: X
authors.lastname: Jiang
authors.affiliation: a subsidiary of Merck KGaA, D-64293 Darmstadt, Germany.
authors.forename: Henry
authors.initials: H
authors.lastname: Hess
authors.affiliation: the EMD Serono Research and Development Institute, Billerica, Massachusetts 01821.
authors.forename: Seng-Lai
authors.initials: SL
authors.lastname: Tan
authors.affiliation: From the Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland, pascal.schneider@unil.ch.
authors.forename: Pascal
authors.initials: P
authors.lastname: Schneider
mesh_terms: D000818:Animals; D053264:B-Cell Activating Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D053265:B-Cell Activation Factor Receptor / Q000235:genetics / Q000378:metabolism; D053301:B-Cell Maturation Antigen / Q000235:genetics / Q000378:metabolism*; D019281:Dimerization; D006801:Humans; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D011485:Protein Binding; D015398:Signal Transduction; D053303:Transmembrane Activator and CAML Interactor Protein / Q000235:genetics / Q000378:metabolism*; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D053301:B-Cell Maturation Antigen; D008024:Ligands; C486361:Tnfrsf13b protein, mouse; C486662:Tnfrsf13c protein, mouse; C490176:Tnfrsf17 protein, mouse; C491959:Tnfsf13 protein, mouse; C505720:Tnfsf13b protein, mouse; D053303:Transmembrane Activator and CAML Interactor Protein; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13
keywords: APRIL; BAFF; cytokine; heteromers; immunology; protein engineering; receptor; signaling