title: Critical role of B cell lymphoma 10 in BAFF-regulated NF-κB activation and survival of anergic B cells.
abstract: Anergy is a key physiological mechanism for restraining self-reactive B cells. A marked portion of peripheral B cells are anergic B cells that largely depend on BAFF for survival. BAFF activates the canonical and noncanonical NF-κB pathways, both of which are required for B cell survival. In this study we report that deficiency of the adaptor protein B cell lymphoma 10 (Bcl10) impaired the ability of BAFF to support B cell survival in vitro, and it specifically increased apoptosis in anergic B cells in vivo, dramatically reducing anergic B cells in mice. Bcl10-dependent survival of self-reactive anergic B cells was confirmed in the Ig hen egg lysozyme/soluble hen egg lysozyme double-transgenic mouse model of B cell anergy. Furthermore, we found that BAFF stimulation induced Bcl10 association with IκB kinase β, a key component of the canonical NF-κB pathway. Consistently, Bcl10-deficient B cells were impaired in BAFF-induced IκBα phosphorylation and formation of nuclear p50/c-Rel complexes. Bcl10-deficient B cells also displayed reduced expression of NF-κB2/p100, severely reducing BAFF-induced nuclear accumulation of noncanonical p52/RelB complexes. Consequently, Bcl10-deficient B cells failed to express Bcl-x(L), a BAFF-induced NF-κB target gene. Taken together, these data demonstrate that Bcl10 controls BAFF-induced canonical NF-κB activation directly and noncanonical NF-κB activation indirectly. The BAFF-R/Bcl10/NF-κB signaling axis plays a critical role in peripheral B cell tolerance by regulating the survival of self-reactive anergic B cells.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China.
authors.forename: Mei
authors.initials: M
authors.lastname: Yu
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Chen
authors.forename: Yinghong
authors.initials: Y
authors.lastname: He
authors.forename: Andrew
authors.initials: A
authors.lastname: Podd
authors.forename: Guoping
authors.initials: G
authors.lastname: Fu
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Wright
authors.forename: Eden
authors.initials: E
authors.lastname: Kleiman
authors.forename: Wasif N
authors.initials: WN
authors.lastname: Khan
authors.forename: Renren
authors.initials: R
authors.lastname: Wen
authors.forename: Demin
authors.initials: D
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D000818:Animals; D017209:Apoptosis; D053264:B-Cell Activating Factor / Q000235:genetics / Q000276:immunology*; D000074018:B-Cell CLL-Lymphoma 10 Protein; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics / Q000276:immunology*; D017635:Clonal Anergy; D005786:Gene Expression Regulation / Q000276:immunology; D051550:I-kappa B Kinase / Q000235:genetics / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D009113:Muramidase / Q000276:immunology; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology*; D052003:NF-kappa B p52 Subunit / Q000235:genetics / Q000276:immunology; D010766:Phosphorylation; D020569:Proto-Oncogene Proteins c-rel / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051841:Transcription Factor RelB / Q000235:genetics / Q000276:immunology; D051020:bcl-X Protein / Q000235:genetics / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D053264:B-Cell Activating Factor; D000074018:B-Cell CLL-Lymphoma 10 Protein; C488088:Bcl10 protein, mouse; C494812:Bcl2l1 protein, mouse; D016328:NF-kappa B; D052003:NF-kappa B p52 Subunit; D020569:Proto-Oncogene Proteins c-rel; C497594:Relb protein, mouse; C505720:Tnfsf13b protein, mouse; D051020:bcl-X Protein; D051841:Transcription Factor RelB; D051550:I-kappa B Kinase; C421864:hen egg lysozyme; D009113:Muramidase