Article

Regulation of CD45 Alternative Splicing by Heterogeneous Ribonucleoprotein, hnRNPLL

Department of Pathology, Immune Disease Institute, Harvard Medical School, Boston, MA 02115, USA.
Science (Impact Factor: 33.61). 09/2008; 321(5889):686-91. DOI: 10.1126/science.1157610
Source: PubMed

ABSTRACT

The transition from naïve to activated T cells is marked by alternative splicing of pre-mRNA encoding the transmembrane phosphatase
CD45. Using a short hairpin RNA interference screen, we identified heterogeneous ribonucleoprotein L-like (hnRNPLL) as a critical
inducible regulator of CD45 alternative splicing. HnRNPLL was up-regulated in stimulated T cells, bound CD45 transcripts,
and was both necessary and sufficient for CD45 alternative splicing. Depletion or overexpression of hnRNPLL in B and T cell
lines and primary T cells resulted in reciprocal alteration of CD45RA and RO expression. Exon array analysis suggested that
hnRNPLL acts as a global regulator of alternative splicing in activated T cells. Induction of hnRNPLL during hematopoietic
cell activation and differentiation may allow cells to rapidly shift their transcriptomes to favor proliferation and inhibit
cell death.

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Available from: Luis F. Moita, Jan 05, 2015
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    • "In addition , the expression levels of genes encoding distinct interleukins are shown in Figure S4d. Finally, confirming the purity of the performed cell sorts, naturally occurring T N , T SCM and in vitro induced T SCM cells expressed similarly low amounts of HNRPLL, a key regulator of the alternative splicing of the CD45 pre-mRNA (Oberdoerffer et al., 2008). Additionally, FAS was among the most significantly differentially expressed genes between naturally occurring T N and T SCM cells (Figure S4e). "
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    • "Silencing of Ptprc exons 4, 5 and 6 in T cells requires hnRNPLL, a protein with three RNA-recognition motif (RRM) domains whose mRNA expression correlates with Ptprc exon exclusion: it is highest in CD45RO+ activated and memory T cells that exclude exons 4 to 6, at intermediate levels in CD45RB+ naïve T cells, and at very low levels in CD45RABC+ B cells that include all three exons [15-17]. Mice homozygous for a destabilizing point mutation in the amino-terminal RRM domain, Hrnpllthu, fail to exclude exons 4, 5, and 6 in T-cell Ptprc mRNA and expression of CD45-RA and CD45-RC protein isoforms are increased 50-fold on different T-cell subsets [16]. "
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