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 found 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 were impaired in CSR activity in vivo and in vitro. Phosphoproteomic screens and kinase-activity assays identified 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 seeding, DYRK1A was required for proper clonal expansion of antigen-specific B cells through attenuation of proliferation. These findings reveal DYRK1A-mediated biological mechanisms of B cell immune responses that may be used for manipulation in antibody-mediated autoimmunity.

Insights from the protein interaction Universe of the multifunctional “Goldilocks” kinase DYRK1A

“…In this model, a Dyrk1a-mediated turnover of cyclin D3 served as a key mechanism for the proper transition from a proliferative state to quiescence. Furthermore, studies using mouse genetic models found that Dyrk1a plays an important role in mature B-cell function in response to infection or vaccination by regulation of class-switch recombination mediated by phosphorylation of mutS homolog 6 (MSH6) protein (Stoler-Barak et al, 2023). MSH6 is a part of a mismatch recognition complex that is mutated in several types of cancer, including the hereditary Lynch syndrome (Abildgaard et al, 2023).…”