Abstract
By alternative splicing, different isoforms of the transmembrane tyrosine phosphatase CD45 are generated that either enhance or limit T cell receptor signaling. We report here that CD45 alternative splicing is regulated by cooperative action of the splice factor U2AF26 and the transcription factor Gfi1. U2AF26 promoted formation of the less-active CD45RO by facilitating exon exclusion. Gfi1 antagonized that process by directly interacting with U2AF26, identifying a previously unknown link between a transcription factor and alternative splicing. The presence of Gfi1 led to formation of the more-active CD45RB, whereas loss of Gfi1 favored CD45RO production. We propose that the relative abundance of U2AF26 and Gfi1 determines the ratio of CD45 isoforms, thereby regulating T cell activation.
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Acknowledgements
We thank I. Spratte, A. Warda and W. Wegrzyn for technical assistance; P. Plessow and T. Civela for animal care; and A. Weiss (University of California, San Francisco, California) and R. Lührmann (Max Planck Institute for Biophysical Chemistry, Gottingen, Germany) for critically reading the manuscript and for suggestions. Supported by the Deutsche Forschungsgemeinschaft (Mo 435/10-4, 10-5), Fonds der Chemischen Industrie, the IFORES Program of the University of Essen Medical School, and Studienstiftung des deutschen Volkes (F.H.).
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G.t.D. provided essential reagents and helped to write the paper; F.H. did the experimental work; F.H. and T.M. designed the experiments, analyzed the data and wrote the paper; and T.M. supervised the work.
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Supplementary information
Supplementary Fig. 1
Mapping of interaction domains in Gfi1 and U2AF26. (PDF 260 kb)
Supplementary Fig. 2
Real-time PCR for the detection of different CD45 isoforms. (PDF 256 kb)
Supplementary Fig. 3
U2AF26-Flag transgene expression is downregulated after T cell stimulation. (PDF 145 kb)
Supplementary Fig. 4
Phenotype of U2AF26 transgenic T cells was indistinguishable from WT T cells. (PDF 458 kb)
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Heyd, F., ten Dam, G. & Möröy, T. Auxiliary splice factor U2AF26 and transcription factor Gfi1 cooperate directly in regulating CD45 alternative splicing. Nat Immunol 7, 859–867 (2006). https://doi.org/10.1038/ni1361
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DOI: https://doi.org/10.1038/ni1361
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