title: Clathrin light chains' role in selective endocytosis influences antibody isotype switching.
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.
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94143; Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94143; Department of Microbiology and Immunology, University of California, San Francisco, CA 94143; The G. W. Hooper Foundation, University of California, San Francisco, CA 94143;
authors.forename: Shuang
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94143; Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94143; Department of Microbiology and Immunology, University of California, San Francisco, CA 94143; The G. W. Hooper Foundation, University of California, San Francisco, CA 94143;
authors.forename: Sophia R
authors.initials: SR
authors.lastname: Majeed
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94143; Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94143; Department of Microbiology and Immunology, University of California, San Francisco, CA 94143; The G. W. Hooper Foundation, University of California, San Francisco, CA 94143;
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Evans
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94143; Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94143; Department of Microbiology and Immunology, University of California, San Francisco, CA 94143; The G. W. Hooper Foundation, University of California, San Francisco, CA 94143; Division of Biosciences, University College London, London WC1E 6BT, United Kingdom;
authors.forename: Marine D
authors.initials: MD
authors.lastname: Camus
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94143; Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94143; Department of Microbiology and Immunology, University of California, San Francisco, CA 94143; The G. W. Hooper Foundation, University of California, San Francisco, CA 94143;
authors.forename: Nicole M L
authors.initials: NM
authors.lastname: Wong
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94143; Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94143; Department of Microbiology and Immunology, University of California, San Francisco, CA 94143; The G. W. Hooper Foundation, University of California, San Francisco, CA 94143;
authors.forename: Yvette
authors.initials: Y
authors.lastname: Schollmeier
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94143; Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94143; Department of Microbiology and Immunology, University of California, San Francisco, CA 94143; The G. W. Hooper Foundation, University of California, San Francisco, CA 94143;
authors.forename: Minjong
authors.initials: M
authors.lastname: Park
authors.affiliation: Department of Microbiology and Immunology, University of California, San Francisco, CA 94143;
authors.forename: Jagan R
authors.initials: JR
authors.lastname: Muppidi
authors.affiliation: Department of Microbiology and Immunology, University of California, San Francisco, CA 94143;
authors.forename: Andrea
authors.initials: A
authors.lastname: Reboldi
authors.affiliation: Department of Structural Biology, Stanford University, Stanford, CA 94305; Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305.
authors.forename: Peter
authors.initials: P
authors.lastname: Parham
authors.affiliation: Department of Microbiology and Immunology, University of California, San Francisco, CA 94143; f.brodsky@ucl.ac.uk jason.cyster@ucsf.edu.
authors.forename: Jason G
authors.initials: JG
authors.lastname: Cyster
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94143; Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94143; Department of Microbiology and Immunology, University of California, San Francisco, CA 94143; The G. W. Hooper Foundation, University of California, San Francisco, CA 94143; Division of Biosciences, University College London, London WC1E 6BT, United Kingdom; f.brodsky@ucl.ac.uk jason.cyster@ucsf.edu.
authors.forename: Frances M
authors.initials: FM
authors.lastname: Brodsky
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002540:Cerebral Cortex / Q000166:cytology / Q000276:immunology; D033941:Clathrin Light Chains / Q000235:genetics* / Q000276:immunology; D004705:Endocytosis / Q000276:immunology*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006801:Humans; D007070:Immunoglobulin A / Q000096:biosynthesis / Q000235:genetics; D017578:Immunoglobulin Class Switching; D008099:Liver / Q000166:cytology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000166:cytology / Q000276:immunology; D009928:Organ Specificity; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000276:immunology; D019718:Receptors, CXCR4 / Q000235:genetics / Q000276:immunology; D017465:Receptors, Opioid, delta / Q000235:genetics / Q000276:immunology; D018125:Receptors, Transforming Growth Factor beta / Q000819:agonists / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology
chemical_list: C514936:CXCR4 protein, mouse; D033941:Clathrin Light Chains; D007070:Immunoglobulin A; D018343:Receptors, Adrenergic, beta-2; D019718:Receptors, CXCR4; D017465:Receptors, Opioid, delta; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
keywords: G protein-coupled receptors; TGFβ; antibody isotype switch; clathrin light chain; endocytosis