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; Edgar Meinl

doi:10.1038/ncomms8333

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 HohlfeldStefan F. Lichtenthaler, Edgar Meinl

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303 Scopus citations

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-kB 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.

Original language	English
Article number	7333
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms8333
State	Published - 11 Jun 2015

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Laurent, S. A., Hoffmann, F. S., Kuhn, P. H., Cheng, Q., Chu, Y., Schmidt-Supprian, M., Hauck, S. M., Schuh, E., Krumbholz, M., Rübsamen, H., Wanngren, J., Khademi, M., Olsson, T., Alexander, T., Hiepe, F., Pfister, H. W., Weber, F., Jenne, D., Wekerle, H., ... Meinl, E. (2015). γ-secretase directly sheds the survival receptor BCMA from plasma cells. Nature Communications, 6, Article 7333. https://doi.org/10.1038/ncomms8333

@article{5fe77e22f5464634b65087c51b3c665b,

title = "γ-secretase directly sheds the survival receptor BCMA from plasma cells",

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-kB 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.",

author = "Laurent, {Sarah A.} and Hoffmann, {Franziska S.} and Kuhn, {Peer Hendrik} and Qingyu Cheng and Yuanyuan Chu and Marc Schmidt-Supprian and Hauck, {Stefanie M.} and Elisabeth Schuh and Markus Krumbholz and Heike R{\"u}bsamen and Johanna Wanngren and Mohsen Khademi and Tomas Olsson and Tobias Alexander and Falk Hiepe and Pfister, {Hans Walter} and Frank Weber and Dieter Jenne and Hartmut Wekerle and Reinhard Hohlfeld and Lichtenthaler, {Stefan F.} and Edgar Meinl",

year = "2015",

month = jun,

day = "11",

doi = "10.1038/ncomms8333",

language = "English",

volume = "6",

journal = "Nature Communications",

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Laurent, SA, Hoffmann, FS, Kuhn, PH, Cheng, Q, Chu, Y, Schmidt-Supprian, M, Hauck, SM, Schuh, E, Krumbholz, M, Rübsamen, H, Wanngren, J, Khademi, M, Olsson, T, Alexander, T, Hiepe, F, Pfister, HW, Weber, F, Jenne, D, Wekerle, H, Hohlfeld, R, Lichtenthaler, SF & Meinl, E 2015, 'γ-secretase directly sheds the survival receptor BCMA from plasma cells', Nature Communications, vol. 6, 7333. https://doi.org/10.1038/ncomms8333

TY - JOUR

T1 - γ-secretase directly sheds the survival receptor BCMA from plasma cells

AU - Laurent, Sarah A.

AU - Hoffmann, Franziska S.

AU - Kuhn, Peer Hendrik

AU - Cheng, Qingyu

AU - Chu, Yuanyuan

AU - Schmidt-Supprian, Marc

AU - Hauck, Stefanie M.

AU - Schuh, Elisabeth

AU - Krumbholz, Markus

AU - Rübsamen, Heike

AU - Wanngren, Johanna

AU - Khademi, Mohsen

AU - Olsson, Tomas

AU - Alexander, Tobias

AU - Hiepe, Falk

AU - Pfister, Hans Walter

AU - Weber, Frank

AU - Jenne, Dieter

AU - Wekerle, Hartmut

AU - Hohlfeld, Reinhard

AU - Lichtenthaler, Stefan F.

AU - Meinl, Edgar

PY - 2015/6/11

Y1 - 2015/6/11

N2 - 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-kB 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.

AB - 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-kB 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.

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DO - 10.1038/ncomms8333

M3 - Article

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AN - SCOPUS:84931291652

SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 7333

ER -

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

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