title: γ-Secretase directly sheds the survival receptor BCMA from plasma cells.
abstract: Survival of plasma cells is regulated by B-cell maturation antigen (BCMA), a membrane-bound receptor activated by its agonist ligands BAFF and APRIL. Here we report that γ-secretase directly cleaves BCMA, without prior truncation by another protease. This direct shedding is facilitated by the short length of BCMA's extracellular domain. In vitro, γ-secretase reduces BCMA-mediated NF-κB activation. In addition, γ-secretase releases soluble BCMA (sBCMA) that acts as a decoy neutralizing APRIL. In vivo, inhibition of γ-secretase enhances BCMA surface expression in plasma cells and increases their number in the bone marrow. Furthermore, in multiple sclerosis, sBCMA levels in spinal fluid are elevated and associated with intracerebral IgG production; in systemic lupus erythematosus, sBCMA levels in serum are elevated and correlate with disease activity. Together, shedding of BCMA by γ-secretase controls plasma cells in the bone marrow and yields a potential biomarker for B-cell involvement in human autoimmune diseases.
authors.affiliation: Institute of Clinical Neuroimmunology, Ludwig Maximilian University Munich, 81377 Munich, Germany.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Laurent
authors.affiliation: Institute of Clinical Neuroimmunology, Ludwig Maximilian University Munich, 81377 Munich, Germany.
authors.forename: Franziska S
authors.initials: FS
authors.lastname: Hoffmann
authors.affiliation: 1] Neuroproteomics, Klinikum rechts der Isar, and Institute of Advanced Study, Technische Universität München, 81377 Munich, Germany [2] German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany.
authors.forename: Peer-Hendrik
authors.initials: PH
authors.lastname: Kuhn
authors.affiliation: Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin and Deutsches Rheuma-Forschungszentrum Berlin-a Leibniz Institute, 10117 Berlin, Germany.
authors.forename: Qingyu
authors.initials: Q
authors.lastname: Cheng
authors.affiliation: Department of Internal Medicine III, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Chu
authors.affiliation: Department of Internal Medicine III, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Schmidt-Supprian
authors.affiliation: Research Unit Protein Science, Helmholtz Zentrum München (GmbH), German Research Center for Environmental Health, 85764 Neuherberg, Germany.
authors.forename: Stefanie M
authors.initials: SM
authors.lastname: Hauck
authors.affiliation: Institute of Clinical Neuroimmunology, Ludwig Maximilian University Munich, 81377 Munich, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Schuh
authors.affiliation: Institute of Clinical Neuroimmunology, Ludwig Maximilian University Munich, 81377 Munich, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Krumbholz
authors.affiliation: Institute of Clinical Neuroimmunology, Ludwig Maximilian University Munich, 81377 Munich, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Rübsamen
authors.affiliation: 1] Neuroproteomics, Klinikum rechts der Isar, and Institute of Advanced Study, Technische Universität München, 81377 Munich, Germany [2] German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Wanngren
authors.affiliation: Karolinska University Hospital, Division of Clinical Neuroscience, 17176 Stockholm, Sweden.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Khademi
authors.affiliation: Karolinska University Hospital, Division of Clinical Neuroscience, 17176 Stockholm, Sweden.
authors.forename: Tomas
authors.initials: T
authors.lastname: Olsson
authors.affiliation: Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin and Deutsches Rheuma-Forschungszentrum Berlin-a Leibniz Institute, 10117 Berlin, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Alexander
authors.affiliation: Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin and Deutsches Rheuma-Forschungszentrum Berlin-a Leibniz Institute, 10117 Berlin, Germany.
authors.forename: Falk
authors.initials: F
authors.lastname: Hiepe
authors.affiliation: Department of Neurology, Klinikum Grosshadern, Ludwig Maximilian University Munich, 81377 Munich, Germany.
authors.forename: Hans-Walter
authors.initials: HW
authors.lastname: Pfister
authors.affiliation: Max-Planck-Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Weber
authors.affiliation: CPC Helmholtz Zentrum München (GmbH), 81377 Munich, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Jenne
authors.affiliation: 1] Max-Planck-Institute of Neurobiology, 82152 Martinsried, Germany [2] Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Wekerle
authors.affiliation: 1] Institute of Clinical Neuroimmunology, Ludwig Maximilian University Munich, 81377 Munich, Germany [2] Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Hohlfeld
authors.affiliation: 1] Neuroproteomics, Klinikum rechts der Isar, and Institute of Advanced Study, Technische Universität München, 81377 Munich, Germany [2] German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany [3] Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany.
authors.forename: Stefan F
authors.initials: SF
authors.lastname: Lichtenthaler
authors.affiliation: Institute of Clinical Neuroimmunology, Ludwig Maximilian University Munich, 81377 Munich, Germany.
authors.forename: Edgar
authors.initials: E
authors.lastname: Meinl
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053301:B-Cell Maturation Antigen / Q000378:metabolism*; D002454:Cell Differentiation; D057809:HEK293 Cells; D006801:Humans; D010950:Plasma Cells / Q000166:cytology / Q000378:metabolism*
chemical_list: D053301:B-Cell Maturation Antigen; C086966:TNFRSF17 protein, human; D053829:Amyloid Precursor Protein Secretases