Abstract
Clathrin, a cytosolic protein composed of heavy and light chain subunits, assembles into a vesicle coat, controlling receptor-mediated endocytosis. To establish clathrin light chain (CLC) function in vivo, we engineered mice lacking CLCa, the major CLC isoform in B lymphocytes, generating animals with CLC-deficient B cells. In CLCa-null mice, the germinal centers have fewer B cells, and they are enriched for IgA-producing cells. This enhanced switch to IgA production in the absence of CLCa was attributable to increased transforming growth factor β receptor 2 (TGFβR2) signaling resulting from defective endocytosis. Internalization of C-X-C chemokine receptor 4 (CXCR4), but not CXCR5, was affected in CLCa-null B cells, and CLC depletion from cell lines affected endocytosis of the δ-opioid receptor, but not the β2-adrenergic receptor, defining a role for CLCs in the uptake of a subset of signaling receptors. This instance of clathrin subunit deletion in vertebrates demonstrates that CLCs contribute to clathrin's role in vivo by influencing cargo selectivity, a function previously assigned exclusively to adaptor molecules.
Keywords:
G protein-coupled receptors; TGFβ; antibody isotype switch; clathrin light chain; endocytosis.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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B-Lymphocytes / immunology*
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B-Lymphocytes / pathology
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Cerebral Cortex / cytology
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Cerebral Cortex / immunology
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Clathrin Light Chains / genetics*
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Clathrin Light Chains / immunology
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Endocytosis / immunology*
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Gene Deletion*
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Gene Expression Regulation
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Humans
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Immunoglobulin A / biosynthesis
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Immunoglobulin A / genetics
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Immunoglobulin Class Switching*
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Liver / cytology
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Liver / immunology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Myocardium / cytology
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Myocardium / immunology
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Organ Specificity
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / immunology
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Receptor, Transforming Growth Factor-beta Type II
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Receptors, Adrenergic, beta-2 / genetics
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Receptors, Adrenergic, beta-2 / immunology
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Receptors, CXCR4 / genetics
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Receptors, CXCR4 / immunology
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Receptors, Opioid, delta / genetics
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Receptors, Opioid, delta / immunology
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Receptors, Transforming Growth Factor beta / agonists
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Receptors, Transforming Growth Factor beta / genetics
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Receptors, Transforming Growth Factor beta / immunology
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Spleen / cytology
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Spleen / immunology
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T-Lymphocytes / cytology
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T-Lymphocytes / immunology
Substances
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CXCR4 protein, mouse
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Clathrin Light Chains
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Immunoglobulin A
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Receptors, Adrenergic, beta-2
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Receptors, CXCR4
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Receptors, Opioid, delta
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Receptors, Transforming Growth Factor beta
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type II