Clathrin light chains’ role in selective endocytosis influences antibody isotype switching

• Published in: Proceedings of the National Academy of Sciences - PNAS 2016-08, Vol.113 (35), p.9816-9821
• Main Authors: Wu, Shuang, Majeed, Sophia R., Evans, Timothy M., Camus, Marine D., Wong, Nicole M. L., Schollmeier, Yvette, Park, Minjong, Muppidi, Jagan R., Reboldi, Andrea, Parham, Peter, Cyster, Jason G., Brodsky, Frances M.
• Format: Article
• Language: English
• Subjects: Animals; B-Lymphocytes - immunology; B-Lymphocytes - pathology; Biological Sciences; Cellular biology; Cerebral Cortex - cytology; Cerebral Cortex - immunology; Clathrin Light Chains - genetics; Clathrin Light Chains - immunology; Endocytosis - immunology; Gene Deletion; Gene Expression Regulation; Humans; Immunoglobulin A - biosynthesis; Immunoglobulin A - genetics; Immunoglobulin Class Switching; Liver - cytology; Liver - immunology; Lymphocytes; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecules; Myocardium - cytology; Myocardium - immunology; Organ Specificity; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - immunology; Proteins; Receptor, Transforming Growth Factor-beta Type II; Receptors, Adrenergic, beta-2 - genetics; Receptors, Adrenergic, beta-2 - immunology; Receptors, CXCR4 - genetics; Receptors, CXCR4 - immunology; Receptors, Opioid, delta - genetics; Receptors, Opioid, delta - immunology; Receptors, Transforming Growth Factor beta - agonists; Receptors, Transforming Growth Factor beta - genetics; Receptors, Transforming Growth Factor beta - immunology; Rodents; Signal transduction; Spleen - cytology; Spleen - immunology; T-Lymphocytes - cytology; T-Lymphocytes - immunology
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1611189113

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.