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

doi:10.1038/s41467-023-37205-5

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

Weizmann Institute of Science, Bar-Ilan University

Research output: Contribution to journal › Article › peer-review

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
Article number	1462
Number of pages	15
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-37205-5
State	Published - 16 Mar 2023

All Science Journal Classification (ASJC) codes

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General
General Physics and Astronomy

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title = "B cell class switch recombination is regulated by DYRK1A through MSH6 phosphorylation",

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.",

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

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doi = "10.1038/s41467-023-37205-5",

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T1 - B cell class switch recombination is regulated by DYRK1A through MSH6 phosphorylation

AU - Stoler-Barak, Liat

AU - Harris, Ethan

AU - Peres, Ayelet

AU - Hezroni, Hadas

AU - Kuka, Mirela

AU - Di Lucia, Pietro

AU - Grenov, Amalie

AU - Gurwicz, Neta

AU - Kupervaser, Meital

AU - Yip, Bon Ham

AU - Iannacone, Matteo

AU - Yaari, Gur

AU - Crispino, John D.

AU - Shulman, Ziv

PY - 2023/3/16

Y1 - 2023/3/16

N2 - 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.

AB - 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.

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DO - 10.1038/s41467-023-37205-5

M3 - مقالة

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SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1462

ER -

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

Abstract

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