Combined loss of the BH3-only proteins Bim and Bmf restores B-cell development and function in @entity71560 -Ig XXXX .

@entity15938 @entity65975 @entity71560 @entity19 @entity1373 @entity22439 @entity1994 @entity1379 @entity56289
UNASSIGNED: Terminal differentiation of B cells depends on two interconnected survival pathways, elicited by the B-cell receptor (BCR) and the @entity65975 ( @entity65975 ), respectively. Loss of either signaling pathway arrests B-cell development. Although BCR-dependent survival depends mainly on the activation of the v- @entity1994 @entity19 thymoma viral oncogene homolog 1 ( @entity1994 )/PI3-kinase network, @entity15938 / @entity65975 -mediated survival engages non-canonical NF-kB signaling as well as MAPK/extracellular-signal regulated kinase and @entity1994 /PI3-kinase modules to allow proper B-cell development. Plasma cell survival, however, is independent of @entity65975 and regulated by APRIL that signals NF-kB activation via alternative receptors, that is, @entity71560 ( @entity71560 ) or B-cell maturation (BCMA). All these complex signaling events are believed to secure survival by increased expression of anti-apoptotic @entity1379 ( @entity1379 ) family proteins in developing and mature B cells. Curiously, how lack of @entity15938 - or APRIL-mediated signaling triggers B-cell apoptosis remains largely unexplored. Here, we show that two pro-apoptotic members of the ' @entity1379 homology domain 3-only' subgroup of the @entity1379 family, @entity1379 interacting mediator of cell death (Bim) and @entity22439 (Bmf), mediate apoptosis in the context of @entity71560 -Ig overexpression that effectively neutralizes @entity15938 as well as APRIL. Surprisingly, although @entity1379 overexpression triggers B-cell @entity1373 exceeding the one observed in Bim(-/-)Bmf(-/-) @entity19 , @entity1379 transgenic B cells remain susceptible to the effects of @entity71560 -Ig expression in vivo, leading to ameliorated pathology in @entity56289 - @entity1379 @entity19 . Together, our findings shed new light on the molecular machinery restricting B-cell survival during development, normal homeostasis and under pathological conditions. Our data further suggest that @entity1379 antagonists might improve the potency of @entity15938 /APRIL-depletion strategies in B-cell-driven pathologies.Cell Death and Differentiation advance online publication, 20 February 2015; doi:10.1038/cdd.2015.8.
