NF-kappa B1 p50 is required for BLyS attenuation of apoptosis but dispensable for processing of NF-kappa B2 p100 to p52 in quiescent mature B cells.
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-kappaB 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 IkappaBalpha characteristic of the classical NF-kappaB pathway, albeit maintaining IkappaBalpha 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-kappaB pathway. p50 is dispensable for p100 processing. However, it is required to mediate the initial BLyS survival signals and concomitant activation of Bcl-x(L) 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-kappaB pathways and selective downstream antiapoptotic genes.
Hatada
Eunice N
EN
Department of Pathology, Cornell-Rockefeller University-Sloan-Kettering Institute Tri-Institutional MD-PhD Program, Weill Medical College of Cornell University, New York, NY, 10021, USA.
Do
Richard K G
RK
Orlofsky
Amos
A
Liou
Hsiou-Chi
HC
Prystowsky
Michael
M
MacLennan
Ian C M
IC
Caamano
Jorge
J
Chen-Kiang
Selina
S
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D053264:B-Cell Activating Factor; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D020672:I-kappa B Proteins / Q000378:metabolism; D007399:Interphase / Q000235:genetics / Q000276:immunology*; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D052002:NF-kappa B p50 Subunit; D052003:NF-kappa B p52 Subunit; D010766:Phosphorylation; D014176:Protein Biosynthesis; D011499:Protein Processing, Post-Translational / Q000235:genetics / Q000276:immunology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D051020:bcl-X Protein
D053264:B-Cell Activating Factor; C096816:BCL2-related protein A1; C494812:Bcl2l1 protein, mouse; D020672:I-kappa B Proteins; D008565:Membrane Proteins; D015778:Minor Histocompatibility Antigens; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D052003:NF-kappa B p52 Subunit; C000606205:Nfkbia protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; C505720:Tnfsf13b protein, mouse; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D051020:bcl-X Protein; D000072000:NF-KappaB Inhibitor alpha