Act1, a negative regulator in CD40- and BAFF-mediated B cell survival.
TNF receptor (TNFR) superfamily members, CD40, and BAFFR play critical roles in B cell survival and differentiation. Genetic deficiency in a novel adaptor molecule, Act1, for CD40 and BAFF results in a dramatic increase in peripheral B cells, which culminates in lymphadenopathy and splenomegaly, hypergammaglobulinemia, and autoantibodies. While the B ... cell-specific Act1 knockout mice displayed a similar phenotype with less severity, the pathology of the Act1-deficient mice was mostly blocked in CD40-Act1 and BAFF-Act1 double knockout mice. CD40- and BAFF-mediated survival is significantly increased in Act1-deficent B cells, with stronger IkappaB phosphorylation, processing of NF-kappaB2 (p100/p52), and activation of JNK, ERK, and p38 pathways, indicating that Act1 negatively regulates CD40- and BAFF-mediated signaling events. These findings demonstrate that Act1 plays an important role in the homeostasis of B cells by attenuating CD40 and BAFFR signaling.
Mesh Terms:
Animals, Antigens, CD40, Autoantibodies, B-Cell Activating Factor, B-Cell Activation Factor Receptor, B-Lymphocytes, Blotting, Southern, Blotting, Western, Carrier Proteins, Cell Survival, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Hypergammaglobulinemia, I-kappa B Proteins, Immunohistochemistry, Immunoprecipitation, JNK Mitogen-Activated Protein Kinases, Lymphoid Tissue, MAP Kinase Kinase 4, Membrane Proteins, Mice, Mice, Knockout, Mice, Transgenic, Mitogen-Activated Protein Kinase Kinases, NF-kappa B, Receptors, Tumor Necrosis Factor, Signal Transduction, Tumor Necrosis Factor-alpha, p38 Mitogen-Activated Protein Kinases
Animals, Antigens, CD40, Autoantibodies, B-Cell Activating Factor, B-Cell Activation Factor Receptor, B-Lymphocytes, Blotting, Southern, Blotting, Western, Carrier Proteins, Cell Survival, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Hypergammaglobulinemia, I-kappa B Proteins, Immunohistochemistry, Immunoprecipitation, JNK Mitogen-Activated Protein Kinases, Lymphoid Tissue, MAP Kinase Kinase 4, Membrane Proteins, Mice, Mice, Knockout, Mice, Transgenic, Mitogen-Activated Protein Kinase Kinases, NF-kappa B, Receptors, Tumor Necrosis Factor, Signal Transduction, Tumor Necrosis Factor-alpha, p38 Mitogen-Activated Protein Kinases
Immunity
Date: Oct. 01, 2004
PubMed ID: 15485634
View in: Pubmed Google Scholar
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