Abstract
The maturation of immature B cells and the survival of mature B cells is stringently controlled to maintain a diverse repertoire of antibody specificities while avoiding self-reactivity. At the molecular level this is regulated by signaling from membrane Ig and the BAFF-receptor that sustain a pro-survival program of gene expression. Whether and how posttranscriptional mechanisms contribute to B cell maturation and survival remains poorly understood. Here, we show that the polypyrimidine tract binding proteins (PTBP) PTBP1 and PTBP3 bind to a large and overlapping set of transcripts in B cells. Both PTBP1 and PTBP3 bind to introns and exons where they are predicted to regulate alternative splicing. Moreover, they also show high-density of binding to 3' untranslated regions suggesting they influence the transcriptome in diverse ways. We show that PTBP1 and PTBP3 are required in B cells beyond the immature cell stage to sustain transitional B cells and the B1, marginal zone and follicular B cell lineages. Therefore, PTBP1 and PTBP3 promote the maturation of quiescent B cells by regulating gene expression at the posttranscriptional level.
Highlights
The maturation of naïve B cells occurs through discrete stages
PTBP1 and PTBP3 bind redundantly to introns and 3’ untranslated regions (3’-UTRs). Since both PTBP1 and PTBP3 are highly homologous, within their RNA binding domains, we compared their transcriptbinding profile by direct mapping binding sites in the B cell transcriptome using individual-nucleotide resolution UV cross-linking and immunoprecipitation [13]
We found a higher density of PTBP3 binding to 3’-UTRs compared to PTBP1 (Fig. 1C)
Summary
The maturation of naïve B cells occurs through discrete stages. In the bone marrow, developing B cells express IgM at their cell surface and are defined as immature. These B cells migrate to the spleen where they mature through different transitional stages (T1 and T2) [1, 2], express BAFF-receptor and establish a homeostatic survival-circuit dependent upon its ligand [3, 4]. RNA binding proteins (RBP) acting posttranscriptionally determine the quantity and variants of transcripts produced from genes. They regulate where, and in what amounts, mRNAs are translated. The role of these regulatory processes in B cell www.eji-journal.eu
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