Differential requirement of MALT1 for BAFF-induced outcomes in B cell subsets.
B cell activation factor of the TNF family (BAFF) activates noncanonical nuclear factor kappaB (NF-kappaB) heterodimers that promote B cell survival. We show that although MALT1 is largely dispensable for canonical NF-kappaB signaling downstream of the B cell receptor, the absence of MALT1 results in impaired BAFF-induced phosphorylation of NF-kappaB2 (p100), p100 degradation, and RelB nuclear translocation in B220(+) B cells. This corresponds with impaired survival of MALT1(-/-) marginal zone (MZ) but not follicular B cells in response to BAFF stimulation in vitro. MALT1(-/-) MZ B cells also express higher amounts of TRAF3, a known negative regulator of BAFF receptor-mediated signaling, and TRAF3 was found to interact with MALT1. Furthermore, phenotypes associated with overexpression of BAFF, including increased MZ B cell numbers, elevated serum immunoglobulin titers, and spontaneous germinal center formation, were found to be dependent on B cell-intrinsic MALT1 expression. Our results demonstrate a novel role for MALT1 in biological outcomes induced by BAFF-mediated signal transduction.
Tusche
Michael W
MW
Department of Immunology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Ward
Lesley A
LA
Vu
Frances
F
McCarthy
Doug
D
Quintela-Fandino
Miguel
M
Ruland
Jurgen
J
Gommerman
Jennifer L
JL
Mak
Tak W
TW
D000818:Animals; D053264:B-Cell Activating Factor / Q000235:genetics / Q000276:immunology*; D016175:B-Lymphocyte Subsets / Q000276:immunology*; D020169:Caspases / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology*; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D048008:TNF Receptor-Associated Factor 3 / Q000235:genetics / Q000276:immunology; D051841:Transcription Factor RelB / Q000235:genetics / Q000276:immunology
D053264:B-Cell Activating Factor; D009363:Neoplasm Proteins; D011947:Receptors, Antigen, B-Cell; C497594:Relb protein, mouse; D048008:TNF Receptor-Associated Factor 3; C505720:Tnfsf13b protein, mouse; D051841:Transcription Factor RelB; D020169:Caspases; C498509:Malt1 protein, mouse; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein