γ-secretase directly sheds the survival receptor BCMA from plasma cells

Sarah A. Laurent, Franziska S. Hoffmann, Peer-Hendrik Kuhn, Qingyu Cheng, Yuanyuan Chu, Marc Schmidt-Supprian, Stefanie M. Hauck, Elisabeth Schuh, Markus Krumbholz, Heike Rübsamen, Johanna Wanngren, Mohsen Khademi, Tomas Olsson, Tobias Alexander, Falk Hiepe, Hans-Walter Pfister, Frank Weber, Dieter Jenne, Hartmut Wekerle, Reinhard Hohlfeld, Stefan F. Lichtenthaler and Edgar Meinl ()
Additional contact information
Sarah A. Laurent: Institute of Clinical Neuroimmunology, Ludwig Maximilian University Munich
Franziska S. Hoffmann: Institute of Clinical Neuroimmunology, Ludwig Maximilian University Munich
Peer-Hendrik Kuhn: Neuroproteomics, Klinikum rechts der Isar, and Institute of Advanced Study, Technische Universität München
Qingyu Cheng: Charité - Universitätsmedizin Berlin and Deutsches Rheuma-Forschungszentrum Berlin-a Leibniz Institute
Yuanyuan Chu: Klinikum Rechts der Isar, Technische Universität München
Marc Schmidt-Supprian: Klinikum Rechts der Isar, Technische Universität München
Stefanie M. Hauck: Research Unit Protein Science, Helmholtz Zentrum München (GmbH), German Research Center for Environmental Health
Elisabeth Schuh: Institute of Clinical Neuroimmunology, Ludwig Maximilian University Munich
Markus Krumbholz: Institute of Clinical Neuroimmunology, Ludwig Maximilian University Munich
Heike Rübsamen: Institute of Clinical Neuroimmunology, Ludwig Maximilian University Munich
Johanna Wanngren: Neuroproteomics, Klinikum rechts der Isar, and Institute of Advanced Study, Technische Universität München
Mohsen Khademi: Karolinska University Hospital
Tomas Olsson: Karolinska University Hospital
Tobias Alexander: Charité - Universitätsmedizin Berlin and Deutsches Rheuma-Forschungszentrum Berlin-a Leibniz Institute
Falk Hiepe: Charité - Universitätsmedizin Berlin and Deutsches Rheuma-Forschungszentrum Berlin-a Leibniz Institute
Hans-Walter Pfister: Klinikum Grosshadern, Ludwig Maximilian University Munich
Frank Weber: Max-Planck-Institute of Psychiatry
Dieter Jenne: CPC Helmholtz Zentrum München (GmbH)
Hartmut Wekerle: Max-Planck-Institute of Neurobiology
Reinhard Hohlfeld: Institute of Clinical Neuroimmunology, Ludwig Maximilian University Munich
Stefan F. Lichtenthaler: Neuroproteomics, Klinikum rechts der Isar, and Institute of Advanced Study, Technische Universität München
Edgar Meinl: Institute of Clinical Neuroimmunology, Ludwig Maximilian University Munich

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8333

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