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

Author

Listed:
  • 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
    German Center for Neurodegenerative Diseases (DZNE))

  • 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
    German Center for Neurodegenerative Diseases (DZNE))

  • 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
    Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany)

  • Reinhard Hohlfeld

    (Institute of Clinical Neuroimmunology, Ludwig Maximilian University Munich
    Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany)

  • Stefan F. Lichtenthaler

    (Neuroproteomics, Klinikum rechts der Isar, and Institute of Advanced Study, Technische Universität München
    German Center for Neurodegenerative Diseases (DZNE)
    Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany)

  • Edgar Meinl

    (Institute of Clinical Neuroimmunology, Ludwig Maximilian University Munich)

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.

Suggested Citation

  • 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 W, 2015. "γ-secretase directly sheds the survival receptor BCMA from plasma cells," Nature Communications, Nature, vol. 6(1), pages 1-12, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8333
    DOI: 10.1038/ncomms8333
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    Cited by:

    1. Frank Cichocki & Ryan Bjordahl & Jodie P. Goodridge & Sajid Mahmood & Svetlana Gaidarova & Ramzey Abujarour & Zachary B. Davis & Aimee Merino & Katie Tuininga & Hongbo Wang & Akhilesh Kumar & Brian Gr, 2022. "Quadruple gene-engineered natural killer cells enable multi-antigen targeting for durable antitumor activity against multiple myeloma," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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