1. γ-secretase directly sheds the survival receptor BCMA from plasma cells
- Author
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Stefanie M. Hauck, Marc Schmidt-Supprian, Frank Weber, Mohsen Khademi, Dieter E. Jenne, Qingyu Cheng, Peer-Hendrik Kuhn, Markus Krumbholz, Franziska Hoffmann, Sarah Laurent, Hartmut Wekerle, Hans-Walter Pfister, Falk Hiepe, Reinhard Hohlfeld, Yuanyuan Chu, Elisabeth Schuh, Tobias Alexander, Stefan F. Lichtenthaler, Johanna Wanngren, Tomas Olsson, Heike Rübsamen, and Edgar Meinl
- Subjects
medicine.medical_specialty ,Cellular differentiation ,Plasma Cells ,General Physics and Astronomy ,antagonists & inhibitors [Amyloid Precursor Protein Secretases] ,Article ,General Biochemistry, Genetics and Molecular Biology ,Antigen ,Internal medicine ,medicine ,Extracellular ,Humans ,B-Cell Maturation Antigen ,B-cell activating factor ,Receptor ,TNFRSF17 protein, human ,Multidisciplinary ,biology ,Cell Differentiation ,General Chemistry ,metabolism [Plasma Cells] ,metabolism [Amyloid Precursor Protein Secretases] ,ddc ,cytology [Plasma Cells] ,HEK293 Cells ,medicine.anatomical_structure ,Endocrinology ,biology.protein ,Cancer research ,ddc:500 ,metabolism [B-Cell Maturation Antigen] ,Bone marrow ,Amyloid Precursor Protein Secretases ,Amyloid precursor protein secretase - 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., B-cell maturation antigen (BCMA) regulates the survival of B cells and is essential for the maintenance of long-lived plasma cells. Here, the authors show that γ-secretase directly sheds BCMA from the cell surface and therefore regulates the number of plasma cells.
- Published
- 2015