GCN5 and BCR signalling collaborate to induce pre-mature B cell apoptosis through depletion of ICAD and IAP2 and activation of caspase activities.
The antigen binding to the B cell receptor (BCR) of pre-mature B lymphocytes induces their apoptotic cell death, although the binding to BCR of mature B lymphocytes does their activation and proliferation. The former is thought not only to function as a mechanism to exclude B cell clones possessing the ability to react with self-antigen, but also to participate as a defense mechanism from auto-immune diseases. Cross-linking of BCR of pre-mature B cell lines, including the chicken DT40 cell line, with anti-immunoglobulin antibody induces their apoptotic cell death. The PMA/ionomycin treatment, which mimics the BCR stimulation, is used to study intracellular signal transduction of B lymphocytes. Here, by analyzing the GCN5-deficient DT40 cell line, we show that GCN5 and BCR signalling are essential for apoptotic cell death. In addition, GCN5 and BCR signalling control cooperatively pre-mature B cell apoptosis via both depletions of ICAD and IAP2 (inhibitors for apoptosis) and elevations of caspase-8 and caspase-3 activities, resulting in increased activity of CAD (effector for apoptosis) followed by the DNA fragmentation. These findings should be useful in understanding the molecular mechanisms involved in negative selection of B cells as also in auto-immune diseases.
Department of Life Science, Frontier Science Research Center, University of Miyazaki, Kiyotake, Miyazaki, Japan.
Hidehiko
H
Kikuchi
Tatsuo
T
Nakayama
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D002645:Chickens / Q000276:immunology; D004789:Enzyme Activation; D017353:Gene Deletion; D005786:Gene Expression Regulation; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D015759:Ionomycin / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D054448:Precursor Cells, B-Lymphoid / Q000187:drug effects / Q000276:immunology*; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
D051017:Apoptosis Regulatory Proteins; D020169:Caspases; D051034:Inhibitor of Apoptosis Proteins; D015759:Ionomycin; D016328:NF-kappa B; D011493:Protein Kinase C; D011947:Receptors, Antigen, B-Cell; D013755:Tetradecanoylphorbol Acetate; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C109664:caspase-activated DNase inhibitor