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Nucleic Acids Res. 2015 Oct 15;43(18):9006-16. doi: 10.1093/nar/gkv816. Epub 2015 Aug 10.

TRAP150 interacts with the RNA-binding domain of PSF and antagonizes splicing of numerous PSF-target genes in T cells.

Author information

1
Department of Biochemistry and Biophysics Perelman, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
2
Department of Cell and Molecular Medicine, University of California, San Diego, San Diego, CA 92093, USA.
3
Department of Biochemistry and Biophysics Perelman, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA klync@mail.med.upenn.edu.

Abstract

PSF (a.k.a. SFPQ) is a ubiquitously expressed, essential nuclear protein with important roles in DNA damage repair and RNA biogenesis. In stimulated T cells, PSF binds to and suppresses the inclusion of CD45 exon 4 in the final mRNA; however, in resting cells, TRAP150 binds PSF and prevents access to the CD45 RNA, though the mechanism for this inhibition has remained unclear. Here, we show that TRAP150 binds a region encompassing the RNA recognition motifs (RRMs) of PSF using a previously uncharacterized, 70 residue region we have termed the PSF-interacting domain (PID). TRAP150's PID directly inhibits the interaction of PSF RRMs with RNA, which is mediated through RRM2. However, interaction of PSF with TRAP150 does not appear to inhibit the dimerization of PSF with other Drosophila Behavior, Human Splicing (DBHS) proteins, which is also dependent on RRM2. Finally, we use RASL-Seq to identify ∼40 T cell splicing events sensitive to PSF knockdown, and show that for the majority of these, PSF's effect is antagonized by TRAP150. Together these data suggest a model in which TRAP150 interacts with dimeric PSF to block access of RNA to RRM2, thereby regulating the activity of PSF toward a broad set of splicing events in T cells.

PMID:
26261210
PMCID:
PMC4605305
DOI:
10.1093/nar/gkv816
[Indexed for MEDLINE]
Free PMC Article

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