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B1 p50 Is Required for BLyS Attenuation of Apoptosis but Dispensable for Processing of NF-B2 p100 to p52 in Quiescent Mature B Cells1
Departments of
*
Pathology,
Microbiology and Immunology, and
Medicine, and
Cornell-Rockefeller University-Sloan-Kettering Institute Tri-Institutional MD-PhD Program, Weill Medical College of Cornell University, New York, NY, 10021;
¶ Albert Einstein College of Medicine, New York, NY 10461; and
|| Medical Research Council Center for Immune Regulation, Birmingham University, Birmingham, U.K.
B lymphocyte stimulator (BLyS), a TNF family protein essential for peripheral B cell development, functions primarily through attenuation of B cell apoptosis. In this study, we show that BLyS activates NF-
B through both classical and alternative pathways with distinct kinetics in quiescent mature B cells. It rapidly and transiently enhances the p50/p65 DNA binding activity and induces phosphorylation of IB
characteristic of the classical NF-B pathway, albeit maintaining IB at a constant level through ongoing protein synthesis and proteasome-mediated destruction. With delayed kinetics, BLyS promotes the processing of p100 to p52 and sustained formation of p52/RelB complexes via the alternative NF-B pathway. p50 is dispensable for p100 processing. However, it is required to mediate the initial BLyS survival signals and concomitant activation of Bcl-xL in quiescent mature B cells ex vivo. Although also a target of BLyS activation, at least one of the A1 genes, A1-a, is dispensable for the BLyS survival function. These results suggest that BLyS mediates its survival signals in metabolically restricted quiescent B cells, at least in part, through coordinated activation of both NF-B pathways and selective downstream antiapoptotic genes.
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