title: BAFF- and TACI-Dependent Processing of BAFFR by ADAM Proteases Regulates the Survival of B Cells.
abstract: B cell activating factor (BAFF) provides B cells with essential survival signals. It binds to three receptors: BAFFR, TACI, and BCMA that are differentially expressed by B cell subsets. BAFFR is early expressed in circulating B cells and provides key signals for further maturation. Here, we report that highly regulated BAFFR processing events modulate BAFF responses. BAFFR processing is triggered by BAFF binding in B cells co-expressing TACI and it is executed by the metalloproteases ADAM10 and ADAM17. The degree of BAFF oligomerization, the expression of ADAM proteins in different B cell subsets, and the activation status of the cell determine the proteases involved in BAFFR processing. Inhibition of ADAM10 augments BAFF-dependent survival of primary human B cells, whereas inhibition of ADAM17 increases BAFFR expression levels on germinal center B cells. Therefore, BAFF-induced processing of BAFFR regulates BAFF-mediated B cell responses in a TACI-dependent manner.
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg im Breisgau, Baden-Württemberg 79106, Germany; Department of Biochemistry, University of Lausanne, Lausanne, Vaud 1066, Switzerland.
authors.forename: Cristian R
authors.initials: CR
authors.lastname: Smulski
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg im Breisgau, Baden-Württemberg 79106, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Kury
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg im Breisgau, Baden-Württemberg 79106, Germany.
authors.forename: Lea M
authors.initials: LM
authors.lastname: Seidel
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg im Breisgau, Baden-Württemberg 79106, Germany.
authors.forename: Hannah S
authors.initials: HS
authors.lastname: Staiger
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg im Breisgau, Baden-Württemberg 79106, Germany.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Edinger
authors.affiliation: Department of Biochemistry, University of Lausanne, Lausanne, Vaud 1066, Switzerland.
authors.forename: Laure
authors.initials: L
authors.lastname: Willen
authors.affiliation: Institute of Clinical Pathology, University Medical Center Freiburg, Freiburg im Breisgau, Baden-Württemberg 79106, Germany.
authors.forename: Maximilan
authors.initials: M
authors.lastname: Seidl
authors.affiliation: Merck KGaA, Darmstadt, Hesse 64293, Germany.
authors.forename: Henry
authors.initials: H
authors.lastname: Hess
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg im Breisgau, Baden-Württemberg 79106, Germany; Department of Rheumatology and Clinical Immunology, Freiburg im Breisgau, Baden-Württemberg 79106, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Salzer
authors.affiliation: Developmental and Molecular Immunology, Department of Biomedicine, University of Basel, Basel-Stadt 4058, Switzerland.
authors.forename: Antonius G
authors.initials: AG
authors.lastname: Rolink
authors.affiliation: Department of Rheumatology and Clinical Immunology, Freiburg im Breisgau, Baden-Württemberg 79106, Germany.
authors.forename: Marta
authors.initials: M
authors.lastname: Rizzi
authors.affiliation: Department of Biochemistry, University of Lausanne, Lausanne, Vaud 1066, Switzerland. Electronic address: pascal.schneider@unil.ch.
authors.forename: Pascal
authors.initials: P
authors.lastname: Schneider
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg im Breisgau, Baden-Württemberg 79106, Germany. Electronic address: hermann.eibel@uniklinik-freiburg.de.
authors.forename: Hermann
authors.initials: H
authors.lastname: Eibel
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D053264:B-Cell Activating Factor / Q000378:metabolism*; D053265:B-Cell Activation Factor Receptor / Q000378:metabolism*; D016175:B-Lymphocyte Subsets / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology*; D006801:Humans; D010447:Peptide Hydrolases / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D053303:Transmembrane Activator and CAML Interactor Protein / Q000378:metabolism*
chemical_list: D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; C108467:TNFRSF13B protein, human; C435926:TNFRSF13C protein, human; C505719:TNFSF13B protein, human; D053303:Transmembrane Activator and CAML Interactor Protein; D010447:Peptide Hydrolases; D051722:ADAM Proteins
keywords: ADAM10; ADAM17; B cell; BAFF-receptor; BAFFR; TACI; ectodomain shedding; germinal center; metalloprotease; processing; survival