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Nat Commun. 2015 Jun 11;6:7333. doi: 10.1038/ncomms8333.

γ-Secretase directly sheds the survival receptor BCMA from plasma cells.

Author information

1
Institute of Clinical Neuroimmunology, Ludwig Maximilian University Munich, 81377 Munich, Germany.
2
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
Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin and Deutsches Rheuma-Forschungszentrum Berlin-a Leibniz Institute, 10117 Berlin, Germany.
4
Department of Internal Medicine III, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany.
5
Research Unit Protein Science, Helmholtz Zentrum München (GmbH), German Research Center for Environmental Health, 85764 Neuherberg, Germany.
6
Karolinska University Hospital, Division of Clinical Neuroscience, 17176 Stockholm, Sweden.
7
Department of Neurology, Klinikum Grosshadern, Ludwig Maximilian University Munich, 81377 Munich, Germany.
8
Max-Planck-Institute of Psychiatry, 80804 Munich, Germany.
9
CPC Helmholtz Zentrum München (GmbH), 81377 Munich, Germany.
10
1] Max-Planck-Institute of Neurobiology, 82152 Martinsried, Germany [2] Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany.
11
1] Institute of Clinical Neuroimmunology, Ludwig Maximilian University Munich, 81377 Munich, Germany [2] Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany.
12
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.

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.

PMID:
26065893
PMCID:
PMC4490565
DOI:
10.1038/ncomms8333
[Indexed for MEDLINE]
Free PMC Article

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