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Auxiliary splice factor U2AF26 and transcription factor Gfi1 cooperate directly in regulating CD45 alternative splicing

Nature Immunology volume 7, pages 859867 (2006) | Download Citation

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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.).

Author information

Author notes

    • Florian Heyd
    •  & Tarik Möröy

    Present address: Institut de Recherches Cliniques de Montréal, Montréal, Québec H2W 1R7, Canada (F.H. and T.M.).

Affiliations

  1. Institut für Zellbiologie (Tumorforschung), Universitätsklinikum Essen, Virchowstrasse 173, D-45122 Essen, Germany.

    • Florian Heyd
    •  & Tarik Möröy
  2. Nijmegen Center for Molecular Life Sciences, 6500 HB Nijmegen, The Netherlands.

    • Gerdy ten Dam

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Contributions

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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Tarik Möröy.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    Mapping of interaction domains in Gfi1 and U2AF26.

  2. 2.

    Supplementary Fig. 2

    Real-time PCR for the detection of different CD45 isoforms.

  3. 3.

    Supplementary Fig. 3

    U2AF26-Flag transgene expression is downregulated after T cell stimulation.

  4. 4.

    Supplementary Fig. 4

    Phenotype of U2AF26 transgenic T cells was indistinguishable from WT T cells.

  5. 5.

    Supplementary Methods

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DOI

https://doi.org/10.1038/ni1361

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