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

Liat Stoler-Barak, Ethan Harris, Ayelet Peres, Hadas Hezroni, Mirela Kuka, Pietro Lucia, Amalie Grenov, Neta Gurwicz, Meital Kupervaser, Bon Ham Yip, Matteo Iannacone, Gur Yaari, John D. Crispino and Ziv Shulman ()
Additional contact information
Liat Stoler-Barak: Weizmann Institute of Science
Ethan Harris: St. Jude Children’s Research Hospital
Ayelet Peres: Bar Ilan University
Hadas Hezroni: Weizmann Institute of Science
Mirela Kuka: Vita-Salute San Raffaele University and Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute
Pietro Lucia: Vita-Salute San Raffaele University and Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute
Amalie Grenov: Weizmann Institute of Science
Neta Gurwicz: Weizmann Institute of Science
Meital Kupervaser: Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science
Bon Ham Yip: St. Jude Children’s Research Hospital
Matteo Iannacone: Vita-Salute San Raffaele University and Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute
Gur Yaari: Bar Ilan University
John D. Crispino: St. Jude Children’s Research Hospital
Ziv Shulman: Weizmann Institute of Science

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37205-5

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