Biology subjects

Screen, M.

Publications and source records attributed to Screen, M..

3 recordsLinked to original sources

bioRxiv2025

RNA helicase DDX1 regulates germinal centre selection and affinity maturation by promoting tRNA ligase activity

Clonal expansion of antigen-specific B-cells defines effective germinal centre responses and is key for the generation of high-affinity antibodies. While positive selection in germinal centres has been associated with anabolic metabolism and cell growth, the downstream drivers of B-cell proliferation are not well understood. Here we report that the RNA helicase DDX1 is required for germinal centre maturation and accrual of dark-zone cellularity. Upon interaction with T-follicular helper cells, DDX1-deficient B-cells upregulate c-MYC but do not clonally expand. We show that positive selection is coupled with an increase in mRNA translation, that is dependent on DDX1. DDX1 endows B-cells with the protein biosynthetic capability that is required for rapid cell proliferation. It does so by modulating the activity of the tRNA ligase complex and tRNA splicing. Our data reveal that mRNA translation efficiency is a key determinant of B-cell fitness during germinal centre responses.

immunology↗

bioRxiv2022

An integrated proteome and transcriptome of B cell maturation defines poised activation states of transitional and mature B cells

During B cell maturation, transitional and mature B cells acquire cell-intrinsic features that determine their ability to exit quiescence and mount effective immune responses. We used label-free mass spectrometry to quantify the proteome of B cell subsets from the mouse spleen and map the differential expression of environmental sensing, transcription- and translation initiation-factors that define cellular identity and function. By comparing the full-length transcriptome and proteome within the same sample, we identified mRNAs linked to B cell activation and antibody secretion that are expressed without detectable protein. These "poised" mRNAs might enable rapid protein production through increased translation or protein stability. In addition, through interrogation of our proteomic dataset, we found that the translational repressor PDCD4 restrains the response of marginal zone B cells to a T-independent antigen. Our molecular characterization of B cell maturation is a valuable resource to further explore the mechanisms underpinning the specialised functions of B cell subsets.

immunology↗

bioRxiv2021

The RNA m6A binding protein YTHDF2 promotes the B cell to plasma cell transition.

To identify roles of RNA binding proteins (RBPs) in the differentiation of B cells to antibody-secreting plasma cells we performed a CRISPR/Cas9 knockout screen of 1213 mouse RBPs for their ability to affect proliferation and/or survival, and the emergence of differentiated CD138+ cells in vitro. We identified RBPs that promoted the appearance of CD138+ cells including CSDE1 and STRAP, as well as RBPs that inhibited CD138+ cell appearance such as EIF3 subunits EIF3K and EIF3L. Furthermore, we identified RBPs that share the property of recruiting the CCR4-NOT complex to their target transcripts have the potential to mediate opposing outcomes on B cell differentiation. One such RBP, the m6A binding protein YTHDF2 promotes the appearance of CD138+ cells in vitro. In chimeric mouse models YTHDF2-deficient B cells formed germinal centers in a cell-autonomous manner, however plasma cells failed to accumulate.

immunology↗