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Schlagwörter:
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Zusammenfassung:
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 gamma-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, gamma-secretase reduces BCMA-mediated NF-kappa B activation. In
addition, gamma-secretase releases soluble BCMA (sBCMA) that acts as a
decoy neutralizing APRIL. In vivo, inhibition of gamma-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 gamma-secretase controls plasma cells in the bone marrow and
yields a potential biomarker for B-cell involvement in human autoimmune
diseases.
