Regulation of B-cell survival by BAFF-dependent PKCdelta-mediated nuclear signalling.
Approximately 65% of B cells generated in human bone marrow are potentially harmful autoreactive B cells. Most of these cells are clonally deleted in the bone marrow, while those autoreactive B cells that escape to the periphery are anergized or perish before becoming mature B cells. Escape of self-reactive B cells from tolerance permits production of pathogenic auto-antibodies; recent studies suggest that extended B lymphocyte survival is a cause of autoimmune disease in mice and humans. Here we report a mechanism for the regulation of peripheral B-cell survival by serine/threonine protein kinase Cdelta (PKCdelta): spontaneous death of resting B cells is regulated by nuclear localization of PKCdelta that contributes to phosphorylation of histone H2B at serine 14 (S14-H2B). We show that treatment of B cells with the potent B-cell survival factor BAFF ('B-cell-activating factor belonging to the TNF family') prevents nuclear accumulation of PKCdelta. Our data suggest the existence of a previously unknown BAFF-induced and PKCdelta-mediated nuclear signalling pathway which regulates B-cell survival.
Mecklenbräuker
Ingrid
I
Laboratory of Lymphocyte Signaling, The Rockefeller University, New York, New York 10021, USA.
Kalled
Susan L
SL
Leitges
Michael
M
Mackay
Fabienne
F
Tarakhovsky
Alexander
A
D000818:Animals; D053264:B-Cell Activating Factor; D001402:B-Lymphocytes / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism*; D016923:Cell Death; D002467:Cell Nucleus / Q000201:enzymology / Q000378:metabolism*; D002470:Cell Survival; D002478:Cells, Cultured; D005347:Fibroblasts; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D011493:Protein Kinase C / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051745:Protein Kinase C-delta; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D053264:B-Cell Activating Factor; D008565:Membrane Proteins; C505719:TNFSF13B protein, human; C505720:Tnfsf13b protein, mouse; D014409:Tumor Necrosis Factor-alpha; C497259:Prkcd protein, mouse; D011493:Protein Kinase C; D051745:Protein Kinase C-delta