Abstract
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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Autoantibodies / blood
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B-Cell Activating Factor
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B-Cell Activation Factor Receptor
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B-Lymphocytes / immunology*
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B-Lymphocytes / metabolism
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Blotting, Southern
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Blotting, Western
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CD40 Antigens / immunology*
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CD40 Antigens / metabolism
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Carrier Proteins / genetics
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Carrier Proteins / immunology
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Carrier Proteins / metabolism*
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Cell Survival / immunology
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Enzyme-Linked Immunosorbent Assay
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Flow Cytometry
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Hypergammaglobulinemia / etiology
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I-kappa B Proteins / immunology
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I-kappa B Proteins / metabolism
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Immunohistochemistry
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Immunoprecipitation
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JNK Mitogen-Activated Protein Kinases / immunology
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JNK Mitogen-Activated Protein Kinases / metabolism
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Lymphoid Tissue / cytology
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Lymphoid Tissue / immunology
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Lymphoid Tissue / pathology
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MAP Kinase Kinase 4
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Membrane Proteins / immunology*
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Membrane Proteins / metabolism
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Mice
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Mice, Knockout
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Mice, Transgenic
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Mitogen-Activated Protein Kinase Kinases / immunology
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Mitogen-Activated Protein Kinase Kinases / metabolism
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NF-kappa B / immunology
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NF-kappa B / metabolism
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Receptors, Tumor Necrosis Factor / immunology
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Receptors, Tumor Necrosis Factor / metabolism
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Signal Transduction / immunology
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Tumor Necrosis Factor-alpha / immunology*
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Tumor Necrosis Factor-alpha / metabolism
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p38 Mitogen-Activated Protein Kinases / immunology
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Autoantibodies
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B-Cell Activating Factor
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B-Cell Activation Factor Receptor
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CD40 Antigens
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Carrier Proteins
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I-kappa B Proteins
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Membrane Proteins
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NF-kappa B
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Receptors, Tumor Necrosis Factor
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TNFRSF13C protein, human
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TNFSF13B protein, human
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Tnfsf13b protein, mouse
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Tumor Necrosis Factor-alpha
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JNK Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 4
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Mitogen-Activated Protein Kinase Kinases