1. Endophilin A2 regulates B‐cell endocytosis and is required for germinal center and humoral responses
- Author
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Pavel Tolar, Laabiah Wasim, Rebecca Newman, Ana Martínez-Riaño, Niklas Engels, and Dessislava Malinova
- Subjects
Endosome ,endophilin A2 ,media_common.quotation_subject ,B‐cell responses ,Immunology ,Antigen presentation ,Infectious Disease ,Endosomes ,Endocytosis ,EMBO20 ,antigen uptake ,Biochemistry ,Article ,Imaging ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,EMBO19 ,Genetics ,medicine ,endocytosis ,Animals ,Membrane & Intracellular Transport ,Internalization ,Endophilin-A2 ,Molecular Biology ,B cell ,030304 developmental biology ,media_common ,B-Lymphocytes ,0303 health sciences ,Chemistry ,FOS: Clinical medicine ,Germinal center ,Cell Biology ,Articles ,Germinal Center ,Clathrin ,Cell biology ,medicine.anatomical_structure ,germinal center ,030217 neurology & neurosurgery ,Structural Biology & Biophysics - Abstract
Antigen‐specific B‐cell responses require endosomal trafficking to regulate antigen uptake and presentation to helper T cells, and to control expression and signaling of immune receptors. However, the molecular composition of B‐cell endosomal trafficking pathways and their specific roles in B‐cell responses have not been systematically investigated. Here, we report high‐throughput identification of genes regulating B‐cell receptor (BCR)‐mediated antigen internalization using genome‐wide functional screens. We show that antigen internalization depends both on constitutive, clathrin‐mediated endocytosis and on antigen‐induced, clathrin‐independent endocytosis mediated by endophilin A2. Although endophilin A2‐mediated endocytosis is dispensable for antigen presentation, it is selectively required for metabolic support of B‐cell proliferation, in part through regulation of iron uptake. Consequently, endophilin A2‐deficient mice show defects in GC B‐cell responses and production of high‐affinity IgG. The requirement for endophilin A2 highlights a unique importance of clathrin‐independent intracellular trafficking in GC B‐cell clonal expansion and antibody responses., A genome‐wide screen reveals a new clathrin‐independent mechanism of antigen uptake in B lymphocytes. The pathway is regulated by endophilin A2, a protein essential for germinal centre expansion and antibody responses.
- Published
- 2021