FOXP3 regulates RNA alternative splicing in regulatory T cells (IRM15P.461)

Abstract

Abstract Alternative pre-mRNA splicing is an important mechanism for protein regulation and cellular function, affecting more than 95% of multi-exon genes in humans and contributing to a wide range of physiological and pathophysiological processes. It is well known that FOXP3, the master transcription factor for Treg differentiation and function, directly binds to its target genes to regulate their transcription. Here we report an interaction between FOXP3 and heterogeneous nuclear ribonucleoprotein F (hnRNPF), a protein that regulates pre-mRNA alternative splicing and/or 3’ polyadenylation. FOXP3 through its exon 2 region interacts with hnRNPF to modulate the alternative splicing pattern of hnRNPF targets like BCL-X. Interestingly, the alternatively spliced exon 2 of human FOXP3 contains hnRNPF putative binding sites and point mutations of these sites eliminate the alternative splicing of human FOXP3. These findings suggest human FOXP3 might autoregulate the alternative splicing of FOXP3 transcripts through its interaction with hnRNPF. Finally, overexpression of hnRNPF in mouse iTregs can reduce their ability to suppress CD4+ T cell proliferation. Taken together, our results reveal a novel molecular mechanism through which FOXP3 modulates pre-mRNA alternative splicing to regulate the differentiation and function of Tregs.