AUTHOR=Bertazzon Miriam , Hurtado-Pico Almudena , Plaza-Sirvent Carlos , Schuster Marc , Preußner Marco , Kuropka Benno , Liu Fan , Kirsten Andor Zenon Amandus , Schmitt Xiao Jakob , König Benjamin , Álvaro-Benito Miguel , Abualrous Esam T. , Albert Gesa I. , Kliche Stefanie , Heyd Florian , Schmitz Ingo , Freund Christian 

TITLE=The nuclear GYF protein CD2BP2/U5–52K is required for T cell homeostasis

JOURNAL=Frontiers in Immunology

VOLUME=Volume 15 - 2024

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1415839

DOI=10.3389/fimmu.2024.1415839

ISSN=1664-3224

ABSTRACT=The question whether interference with the ubiquitous splicing machinery can lead to cell-type specific perturbation of cellular function is addressed here by T cell specific ablation of the general U5 snRNP assembly factor CD2BP2/U5-52K. This protein defines the family of nuclear GYF domain containing proteins that are ubiquitously expressed in eukaryotes with essential functions ascribed to early embryogenesis and organ function. Abrogating CD2BP2/U5-52K in T cells, allows us to delineate the consequences of splicing machinery interferences for T cell development and function. Increased T cell lymphopenia and T cell death are observed upon depletion of CD2BP2/U5-52K. A substantial increase in exon skipping coincides with the observed defect in the proliferation/differentiation balance in the absence of CD2BP2/U5-52K. Prominently, skipping of exon 7 in Mdm4 is observed, coinciding with upregulation of pro-apoptotic gene expression profiles upon CD2BP2/U5-52K depletion. Furthermore, we observe enhanced sensitivity of naïve T cells compared to memory T cells to changes in CD2BP2/U5-52K levels, indicating that that depletion of this general splicing factor leads to modulation of T cell homeostasis.