B cell class switch recombination is regulated by DYRK1A through MSH6 phosphorylation

Liat Stoler-Barak, Ethan Harris, Ayelet Peres, Hadas Hezroni, Mirela Kuka, Pietro Di Lucia, Amalie Grenov, Neta Gurwicz, Meital Kupervaser, Bon Ham Yip, Matteo Iannacone, Gur Yaari, John D. Crispino, Ziv Shulman

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

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 languageEnglish
Article number1462
JournalNature Communications
Volume14
Issue number1
DOIs
StatePublished - 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.

FundersFunder number
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 ProgramCDA-00023/2016
European Molecular Biology Organization
Gerald O. Mann Charitable Foundation
Irma und Jacques Ber-Lehmsdorf - Stiftung
European Commission101001613
Israel Science Foundation1090/18
Azrieli Foundation

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