Abstract
Protection from viral infections depends on immunoglobulin isotype switching, which endows antibodies with effector functions. Here, we find that the protein kinase DYRK1A is essential for B cell-mediated protection from viral infection and effective vaccination through regulation of class switch recombination (CSR). Dyrk1a-deficient B cells are impaired in CSR activity in vivo and in vitro. Phosphoproteomic screens and kinase-activity assays identify MSH6, a DNA mismatch repair protein, as a direct substrate for DYRK1A, and deletion of a single phosphorylation site impaired CSR. After CSR and germinal center (GC) seeding, DYRK1A is required for attenuation of B cell proliferation. These findings demonstrate DYRK1A-mediated biological mechanisms of B cell immune responses that may be used for therapeutic manipulation in antibody-mediated autoimmunity.
Original language | English |
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Article number | 1462 |
Journal | Nature Communications |
Volume | 14 |
Issue number | 1 |
DOIs | |
State | Published - 16 Mar 2023 |
Bibliographical note
Publisher Copyright:© 2023, The Author(s).
Funding
Z.S. is supported by the European Research Council (ERC) grant No. 101001613, by the Morris Kahn Institute for Human Immunology, Human Frontiers of Science Program (CDA-00023/2016), Azrieli Foundation, Israel Science Foundation (ISF, 1090/18). Z.S. is a member of the European Molecular Biology Organization (EMBO) Young Investigator Program. Z.S. is supported by grants from The Benoziyo Endowment Fund for the Advancement of Science, The Sir Charles Clore Research Prize, Comisaroff Family Trust, Irma & Jacques Ber-Lehmsdorf Foundation, Gerald O. Mann Charitable Foundation and David M. Polen Charitable Trust and Elie Hirschfeld and Dr. Sarah Schlesinger. E.H. received support from the ASH Medical Student Physician-Scientist Award. Z.S. is supported by the European Research Council (ERC) grant No. 101001613, by the Morris Kahn Institute for Human Immunology, Human Frontiers of Science Program (CDA-00023/2016), Azrieli Foundation, Israel Science Foundation (ISF, 1090/18). Z.S. is a member of the European Molecular Biology Organization (EMBO) Young Investigator Program. Z.S. is supported by grants from The Benoziyo Endowment Fund for the Advancement of Science, The Sir Charles Clore Research Prize, Comisaroff Family Trust, Irma & Jacques Ber-Lehmsdorf Foundation, Gerald O. Mann Charitable Foundation and David M. Polen Charitable Trust and Elie Hirschfeld and Dr. Sarah Schlesinger. E.H. received support from the ASH Medical Student Physician-Scientist Award.
Funders | Funder number |
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Benoziyo Endowment Fund for the Advancement of Science, The Sir Charles Clore Research Prize | |
Comisaroff Family Trust | |
Morris Kahn Institute for Human Immunology, Human Frontiers of Science Program | CDA-00023/2016 |
European Molecular Biology Organization | |
Gerald O. Mann Charitable Foundation | |
Irma und Jacques Ber-Lehmsdorf - Stiftung | |
European Commission | 101001613 |
Israel Science Foundation | 1090/18 |
Azrieli Foundation |