Original Paper
Cell Death and Differentiation (2007) 14, 1936–1947; doi:10.1038/sj.cdd.4402206; published online 3 August 2007
The novel adaptor protein Swiprosin-1 enhances BCR signals and contributes to BCR-induced apoptosis
Edited by B Osborne
A Avramidou1,2,3, C Kroczek1,2, C Lang1, W Schuh1, H-M Jäck1 and D Mielenz1
1Division of Molecular Immunology, Department of Internal Medicine III, Nikolaus Fiebiger Center for Molecular Medicine, University of Erlangen-Nürnberg, Germany
Correspondence: D Mielenz, Division of Molecular Immunology, Department of Internal Medicine III, Nikolaus Fiebiger Center for Molecular Medicine, Glückstr. 6, Erlangen 91054, Germany. Tel. +49 9131 8539105; Fax +49 9131 8539343; E-mail: dmielenz@molmed.uni-erlangen.de
2These authors contributed equally to this work
3Current address: Department of Haemato-Oncology, Brookes Lawley Building, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Greater London SM2 5NG, UK
Received 20 November 2006; Revised 21 June 2007; Accepted 25 June 2007; Published online 3 August 2007.
Abstract
B-cell receptor (BCR) signals are essential for B-cell differentiation, homeostasis and negative selection, which are regulated by the strength and quality of BCR signals. Recently, we identified a new adaptor protein, Swiprosin-1, in lipid rafts of B-cell lines that undergo apoptosis after BCR stimulation. During murine B-cell development, Swiprosin-1 exhibited highest expression in immature B cells of the bone marrow, but was also expressed in resting and activated splenic B cells and in non-lymphoid tissue, especially in the brain. Ectopic expression of Swiprosin-1 in the immature murine B-cell line WEHI231 enhanced spontaneous and BCR-induced apoptosis. In contrast, short hairpin RNA (shRNA)-mediated downregulation of Swiprosin-1 impaired specifically spontaneous and BCR-elicited apoptosis, but not BCR-induced G1 cell cycle arrest and upregulation of the cell cycle inhibitor p27Kip1. In accordance, Swiprosin-1 abundance regulated net cell growth of WEHI231 cell populations through reciprocal regulation of Bcl-xL, but not Bim, thereby controlling spontaneous apoptosis. Swiprosin-1-enhanced apoptosis was blocked through nuclear factor 
B-activating stimuli, namely B-cell-activating factor of the TNF family, anti-CD40 and lipopolysaccharide (LPS). This correlated with enhanced BCR-induced IB-
phosphorylation and degradation in cells expressing a Swiprosin-1-specific shRNA. Finally, ectopic Swiprosin-1 expression enhanced BCR-induced cell death in primary, LPS-stimulated splenic B cells. Hence, Swiprosin-1 may regulate lifespan and BCR signaling thresholds in immature B cells.
Keywords:
B-cell receptor, B-cell tolerance, apoptosis, cell cycle, cell growth
Abbreviations:
BCR, B-cell receptor; 
Hc, heavy chain; AnxV, Annexin V; PI, propidium iodide; 
m, mitochondrial membrane potential; shRNA, short hairpin RNA; DioC6, 3,3'-dihexyloxacarbocyanine iodide; MAPK, mitogen-activated protein kinase; Erk, extracellular signal-regulated kinase; IB, inhibitor of NF-B; NF-B, nuclear factor B; LPS, lipopolysaccharide; BAFF, B-cell activating factor of the TNF family; PL, phospholipase; PKC, protein kinase C; TLR, toll-like receptor; Sw1, Swiprosin-1
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