BAFF- and TACI-Dependent Processing of BAFFR by ADAM Proteases Regulates the Survival of B Cells

Cristian R Smulski; Patrick Kury; Lea M Seidel; Hannah S Staiger; Anna K Edinger; Laure Willen; Maximilan Seidl; Henry Hess; Ulrich Salzer; Antonius G Rolink; Marta Rizzi; Pascal Schneider; Hermann Eibel

doi:10.1016/j.celrep.2017.02.005

BAFF- and TACI-Dependent Processing of BAFFR by ADAM Proteases Regulates the Survival of B Cells

Cell Rep. 2017 Feb 28;18(9):2189-2202. doi: 10.1016/j.celrep.2017.02.005.

Authors

Affiliations

¹ 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.
² Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg im Breisgau, Baden-Württemberg 79106, Germany.
³ Department of Biochemistry, University of Lausanne, Lausanne, Vaud 1066, Switzerland.
⁴ Institute of Clinical Pathology, University Medical Center Freiburg, Freiburg im Breisgau, Baden-Württemberg 79106, Germany.
⁵ Merck KGaA, Darmstadt, Hesse 64293, Germany.
⁶ 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.
⁷ Developmental and Molecular Immunology, Department of Biomedicine, University of Basel, Basel-Stadt 4058, Switzerland.
⁸ Department of Rheumatology and Clinical Immunology, Freiburg im Breisgau, Baden-Württemberg 79106, Germany.
⁹ Department of Biochemistry, University of Lausanne, Lausanne, Vaud 1066, Switzerland. Electronic address: pascal.schneider@unil.ch.
¹⁰ Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg im Breisgau, Baden-Württemberg 79106, Germany. Electronic address: hermann.eibel@uniklinik-freiburg.de.

PMID: 28249164
DOI: 10.1016/j.celrep.2017.02.005

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.

Keywords: ADAM10; ADAM17; B cell; BAFF-receptor; BAFFR; TACI; ectodomain shedding; germinal center; metalloprotease; processing; survival.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ADAM Proteins / metabolism*
B-Cell Activating Factor / metabolism*
B-Cell Activation Factor Receptor / metabolism*
B-Lymphocyte Subsets / metabolism*
Cell Line
Cell Survival / physiology*
Humans
Peptide Hydrolases / metabolism*
Protein Binding / physiology
Transmembrane Activator and CAML Interactor Protein / metabolism*

Substances

B-Cell Activating Factor
B-Cell Activation Factor Receptor
TNFRSF13B protein, human
TNFRSF13C protein, human
TNFSF13B protein, human
Transmembrane Activator and CAML Interactor Protein
Peptide Hydrolases
ADAM Proteins