CoChat
Sign Up
Cited by 377NF-κB Signaling PathwaysT-cell and B-cell ImmunologyAlzheimer's disease research and treatments

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

Open access
Laurent, Sarah A., Hoffmann, Franziska S., Kuhn, Peer-Hendrik, Cheng, Qingyu, Chu, Yuanyuan, Schmidt-Supprian, Marc, Hauck, Stefanie M., Schuh, Elisabeth +14 more·2015·Nature Communications
DOI 10.1038/ncomms8333PMC PMC4490565
Open this paper in CoChat — free accountOpen PDF

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/ncomms8333

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • γ-secretase controls B cell homeostasis by cleaving BCMA, such that γ-secretase inhibition leads to enhanced BCMA surface expression and expanded plasma cell numbers.

    “γ -secretase also controls B cell homeostasis by cleaving B cell maturation antigen (BCMA), the cognate receptor for the plasma cell survival factors BAFF and APRIL, such that γ -secretase inhibition leads to enhanced BCMA surface expression and expanded plasma cell numbers [15].”

    From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [15]

    The Abstract and Discussion report that γ-secretase cleaves BCMA and that its inhibition enhances BCMA surface expression on plasma cells. The Discussion specifies that plasma cell numbers increased in the bone marrow after seven days of inhibition, but not in the spleen; the claim omits that site restriction. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

No references could be resolved yet.

Research works printed but not linked: 54

  1. Dörner T., Radbruch A. & Burmester G. R. B-cell-directed therapies for autoimmune disease. Nat. Rev. Rheumatol. 5, 433– 441 (2009). 19581902
  2. Krumbholz M., Derfuss T., Hohlfeld R. & Meinl E. B cells and antibodies in multiple sclerosis pathogenesis and therapy. Nat. Rev. Neurol. 8, 613– 623 (2012). 23045237
  3. Mackay F. & Schneider P. Cracking the BAFF code. Nat. Rev. Immunol. 9, 491– 502 (2009). 19521398
  4. Yang M.. B cell maturation antigen, the receptor for a proliferation-inducing ligand and B cell-activating factor of the TNF family, induces antigen presentation in B cells. J. Immunol. 175, 2814– 2824 (2005). 16116167
  5. Darce J. R., Arendt B. K., Wu X. & Jelinek D. F. Regulated expression of BAFF-binding receptors during human B cell differentiation. J. Immunol. 179, 7276– 7286 (2007). 18025170
  6. Avery D. T.. BAFF selectively enhances the survival of plasmablasts generated from human memory B cells. J. Clin. Invest. 112, 286– 297 (2003). 12865416 PMC164292
  7. O'Connor B. P.. BCMA is essential for the survival of long-lived bone marrow plasma cells. J. Exp. Med. 199, 91– 98 (2004). 14707116 PMC1887725
  8. Peperzak V.. Mcl-1 is essential for the survival of plasma cells. Nat. Immunol. 14, 290– 297 (2013). 23377201 PMC4041127
  9. Belnoue E.. APRIL is critical for plasmablast survival in the bone marrow and poorly expressed by early-life bone marrow stromal cells. Blood 111, 2755– 2764 (2008). 18180376
  10. Benson M. J.. Cutting edge: the dependence of plasma cells and independence of memory B cells on BAFF and APRIL. J. Immunol. 180, 3655– 3659 (2008). 18322170
  11. Amanna I. J. & Slifka M. K. Mechanisms that determine plasma cell lifespan and the duration of humoral immunity. Immunol. Rev. 236, 125– 138 (2010). 20636813 PMC7165522
  12. Hiepe F.. Long-lived autoreactive plasma cells drive persistent autoimmune inflammation. Nat. Rev. Rheumatol. 7, 170– 178 (2011). 21283146
  13. Croft M., Benedict C. A. & Ware C. F. Clinical targeting of the TNF and TNFR superfamilies. Nat. Rev. Drug Discov. 12, 147– 168 (2013). 23334208 PMC3625401
  14. Stohl W., Scholz J. L. & Cancro M. P. Targeting BLyS in rheumatic disease: the sometimes-bumpy road from bench to bedside. Curr. Opin. Rheumatol. 23, 305– 310 (2011). 21330926 PMC3154025
  15. Kappos L.. Atacicept in multiple sclerosis (ATAMS): a randomised, placebo-controlled, double-blind, phase 2 trial. Lancet Neurol. 13, 353– 363 (2014). 24613349
  16. Kopan R. & Ilagan M. X. Gamma-secretase: proteasome of the membrane? Nat. Rev. Mol. Cell Biol. 5, 499– 504 (2004). 15173829
  17. Selkoe D. J. & Wolfe M. S. Presenilin: running with scissors in the membrane. Cell 131, 215– 221 (2007). 17956719
  18. Ransohoff R. M. & Engelhardt B. The anatomical and cellular basis of immune surveillance in the central nervous system. Nat. Rev. Immunol. 12, 623– 635 (2012). 22903150
  19. Pinna D., Corti D., Jarrossay D., Sallusto F. & Lanzavecchia A. Clonal dissection of the human memory B-cell repertoire following infection and vaccination. Eur. J. Immunol. 39, 1260– 1270 (2009). 19404981 PMC3864550
  20. Avery D. T.. Increased expression of CD27 on activated human memory B cells correlates with their commitment to the plasma cell lineage. J. Immunol. 174, 4034– 4042 (2005). 15778361
  21. Herreman A.. Total inactivation of gamma-secretase activity in presenilin-deficient embryonic stem cells. Nat. Cell Biol. 2, 461– 462 (2000). 10878813
  22. Yamasaki A.. The GxGD motif of presenilin contributes to catalytic function and substrate identification of gamma-secretase. J. Neurosci. 26, 3821– 3828 (2006). 16597736 PMC6674133
  23. Bossen C. & Schneider P. BAFF, APRIL and their receptors: structure, function and signaling. Semin. Immunol. 18, 263– 275 (2006). 16914324
  24. Luzina I. G.. Spontaneous formation of germinal centers in autoimmune mice. J. Leukoc. Biol. 70, 578– 584 (2001). 11590194
  25. Cassese G.. Inflamed kidneys of NZB/W mice are a major site for the homeostasis of plasma cells. Eur. J. Immunol. 31, 2726– 2732 (2001). 11536171
  26. Yu G.. APRIL and TALL-I and receptors BCMA and TACI: system for regulating humoral immunity. Nat. Immunol. 1, 252– 256 (2000). 10973284
  27. Rennert P.. A soluble form of B cell maturation antigen, a receptor for the tumor necrosis factor family member APRIL, inhibits tumor cell growth. J. Exp. Med. 192, 1677– 1684 (2000). 11104810 PMC2193103
  28. Struhl G. & Adachi A. Requirements for presenilin-dependent cleavage of notch and other transmembrane proteins. Mol. Cell 6, 625– 636 (2000). 11030342
  29. Hemming M. L., Elias J. E., Gygi S. P. & Selkoe D. J. Proteomic profiling of gamma-secretase substrates and mapping of substrate requirements. PLoS Biol. 6, e257 (2008). 18942891 PMC2570425
  30. Day E. S.. Selectivity of BAFF/BLyS and APRIL for binding to the TNF family receptors BAFFR/BR3 and BCMA. Biochemistry (Mosc.) 44, 1919– 1931 (2005). 15697217
  31. Castigli E.. Impaired IgA class switching in APRIL-deficient mice. Proc. Natl Acad. Sci. USA 101, 3903– 3908 (2004). 14988498 PMC374342
  32. Radtke F., MacDonald H. R. & Tacchini-Cottier F. Regulation of innate and adaptive immunity by Notch. Nat. Rev. Immunol. 13, 427– 437 (2013). 23665520
  33. Simonetti G.. IRF4 controls the positioning of mature B cells in the lymphoid microenvironments by regulating NOTCH2 expression and activity. J. Exp. Med. 210, 2887– 2902 (2013). 24323359 PMC3865479
  34. Yoon S. O., Zhang X., Berner P., Blom B. & Choi Y. S. Notch ligands expressed by follicular dendritic cells protect germinal center B cells from apoptosis. J. Immunol. 183, 352– 358 (2009). 19542446
  35. Yagi T.. Defective signal transduction in B lymphocytes lacking presenilin proteins. Proc. Natl Acad. Sci. USA 105, 979– 984 (2008). 18195359 PMC2242696
  36. Levine S. J. Molecular mechanisms of soluble cytokine receptor generation. J. Biol. Chem. 283, 14177– 14181 (2008). 18385130 PMC2386928
  37. Xanthoulea S.. Tumor necrosis factor (TNF) receptor shedding controls thresholds of innate immune activation that balance opposing TNF functions in infectious and inflammatory diseases. J. Exp. Med. 200, 367– 376 (2004). 15289505 PMC2211976
  38. Hoffmann F. S.. The Immunoregulator Soluble TACI Is Released by ADAM10 and Reflects B Cell Activation in Autoimmunity. J. Immunol. 194, 542– 552 (2015). 25505277 PMC4282951
  39. von Budingen H. C., Bar-Or A. & Zamvil S. S. B cells in multiple sclerosis: connecting the dots. Curr. Opin. Immunol. 23, 713– 720 (2011). 21983151 PMC4188435
  40. Nylander A. & Hafler D. A. Multiple sclerosis. J. Clin. Invest. 122, 1180– 1188 (2012). 22466660 PMC3314452
  41. Krumbholz M.. BAFF is produced by astrocytes and up-regulated in multiple sclerosis lesions and primary central nervous system lymphoma. J. Exp. Med. 201, 195– 200 (2005). 15642740 PMC2212784
  42. Cepok S.. Short-lived plasma blasts are the main B cell effector subset during the course of multiple sclerosis. Brain 128, 1667– 1676 (2005). 15800022
  43. Stohl W.. B lymphocyte stimulator overexpression in patients with systemic lupus erythematosus: longitudinal observations. Arthritis Rheum. 48, 3475– 3486 (2003). 14673998
  44. Kim J., Gross J. A., Dillon S. R., Min J. K. & Elkon K. B. Increased BCMA expression in lupus marks activated B cells, and BCMA receptor engagement enhances the response to TLR9 stimulation. Autoimmunity 44, 69– 81 (2011). 21250838
  45. Vincent F. B., Saulep-Easton D., Figgett W. A., Fairfax K. A. & Mackay F. The BAFF/APRIL system: emerging functions beyond B cell biology and autoimmunity. Cytokine Growth Factor Rev. 24, 203– 215 (2013). 23684423 PMC7108297
  46. Osorio C.. Selective regulation of axonal growth from developing hippocampal neurons by tumor necrosis factor superfamily member APRIL. Mol. Cell Neurosci. 59C, 24– 36 (2014). 24444792 PMC4008386
  47. Sanchez E.. Serum B-cell maturation antigen is elevated in multiple myeloma and correlates with disease status and survival. Br. J. Haematol. 158, 727– 738 (2012). 22804669
  48. Minter L. M.. Inhibitors of gamma-secretase block in vivo and in vitro T helper type 1 polarization by preventing Notch upregulation of Tbx21. Nat. Immunol. 6, 680– 688 (2005). 15991363
  49. Burger R.. Interleukin-6 production in B-cell neoplasias and Castleman's disease: evidence for an additional paracrine loop. Ann. Hematol. 69, 25– 31 (1994). 8061104
  50. Hauck S. M.. Deciphering membrane-associated molecular processes in target tissue of autoimmune uveitis by label-free quantitative mass spectrometry. Mol. Cell Proteomics 9, 2292– 2305 (2010). 20601722 PMC2953921
  51. Mitterreiter S.. Bepridil and amiodarone simultaneously target the Alzheimer's disease beta- and gamma-secretase via distinct mechanisms. J. Neurosci. 30, 8974– 8983 (2010). 20592218 PMC6632893
  52. Perera N. C.. NSP4 is stored in azurophil granules and released by activated neutrophils as active endoprotease with restricted specificity. J. Immunol. 191, 2700– 2707 (2013). 23904161
  53. Pasare C. & Medzhitov R. Control of B-cell responses by Toll-like receptors. Nature 438, 364– 368 (2005). 16292312
  54. Hoyer B. F.. Short-lived plasmablasts and long-lived plasma cells contribute to chronic humoral autoimmunity in NZB/W mice. J. Exp. Med. 199, 1577– 1584 (2004). 15173206 PMC2211779

Cited by

Sorted by citations

Authors
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., Hohlfeld, R., Lichtenthaler, S. F., & Meinl, E.
Affiliations
  • Institut für Klinische Neuroimmunologie (DE)
  • German Center for Neurodegenerative Diseases (DE)
  • German Rheumatism Research Centre (DE)
  • TUM Klinikum (DE)
  • Helmholtz Munich (DE)
  • Karolinska University Hospital (SE)
  • LMU Klinikum (DE)
  • Max Planck Institute of Psychiatry (DE)
  • Munich Cluster for Systems Neurology (DE)
Corresponding author
Meinl, Edgar
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2015-06-11
Volume
6
Issue
1
Pages
7333-7333
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/ncomms8333
PMC
PMC4490565
OpenAlex
W1661103064
Cited by
377
References
0
Citations by year
2026: 38 · 2025: 35 · 2024: 47 · 2023: 42 · 2022: 50 · 2021: 43 · 2020: 49 · 2019: 30 · 2018: 18 · 2017: 18 · 2016: 4 · 2015: 3
FWCI
4.74
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DZNE Pub (publishedVersion, other-oa)
  • Elektronische Hochschulschriften der LMU München (Ludwig-Maximilians-Universität München) (submittedVersion)
  • MPG.PuRe (Max Planck Society) (submittedVersion, cc-by)
  • PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion)
  • mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
  • Site cant be reached (submittedVersion, cc-by)
Funders
  • EU Joint Programme – Neurodegenerative Disease Research
  • Deutsche Forschungsgemeinschaft (SFB/TRR 128, TRR130, SFB 650)
  • Bundesministerium für Bildung und Forschung (TRR 130)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
gamma-secretase, BCMA, plasma cells, receptor shedding, soluble BCMA, APRIL, BAFF, NF-κB activation, multiple sclerosis, systemic lupus erythematosus, autoimmune disease biomarkers, intrathecal IgG
MeSH terms
Cell Differentiation, Humans, Plasma Cells, B-Cell Maturation Antigen, Amyloid Precursor Protein Secretases, HEK293 Cells

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review