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RNA-binding proteins regulate the expression of the immune activating ligand MICB

Nature Communications volume 5, Article number: 4186 (2014) | Download Citation

Abstract

The recognition of stress-induced ligands by the activating receptor NKG2D expressed on cytotoxic lymphocytes is crucial for the prevention and containment of various diseases and is also one of the best-studied examples of how danger is sensed by the immune system. Still, however, the mechanisms leading to the expression of the NKG2D ligands are far from being completely understood. Here, we use an unbiased and systematic RNA pull-down approach combined with mass spectrometry to identify six RNA-binding proteins (RBPs) that bind and regulate the expression of MICB, one of the major stress-induced ligands of NKG2D. We further demonstrate that at least two of the identified RBPs function during genotoxic stress. Our data provide insights into stress recognition and hopefully open new therapeutic venues.

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Acknowledgements

This study was supported by the MOST-DKFZ Cooperation programme (Ca-135, to O.M. and S.D.) and funding from the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013)/ERC Grant Agreement number 320473-BacNK. Further support came from the GIF foundation, from the Lewis family foundation, the ICRF professorship grant, the Israeli Science Foundation and the Rosetrees Trust (all to O.M.). O.M. is a Crown Professor of Molecular Immunology. D.N. is supported by the Adams Fellowship Programme of the Israel Academy of Sciences and Humanities. Research in the Diederichs Lab is supported by the Helmholtz Society (VH-NG-504), the Excellence Cluster CellNetworks, and the Virtual Helmholtz Institute for Resistance in Leukaemia. The authors thank Yoav Livneh for fruitful discussions.

Author information

Author notes

    • Sven Diederichs
    •  & Ofer Mandelboim

    These authors contributed equally to this work

    • Tony Gutschner

    Present address: UT MD Anderson Cancer Center, Department of Genomic Medicine, Division of Cancer Medicine, Houston, 77054 TX, USA

Affiliations

  1. The Lautenberg Center for General and Tumor Immunology, The BioMedical Research Institute Israel Canada of the Faculty of Medicine, The Hebrew University Hadassah Medical School, 91120 Jerusalem, Israel

    • Daphna Nachmani
    • , Adi Reches
    •  & Ofer Mandelboim
  2. Helmholtz-University-Group "Molecular RNA Biology & Cancer", German Cancer Research Center DKFZ and Institute of Pathology, University Hospital Heidelberg, D-69120 Heidelberg, Germany

    • Tony Gutschner
    •  & Sven Diederichs

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Contributions

D.N. designed and performed the experiments, analysed the data and wrote the manuscript; D.N. and T.G. performed the RNA-AP and wrote the manuscript; A.R. provided reagents; S.D. and O.M. supervised the project and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Ofer Mandelboim.

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DOI

https://doi.org/10.1038/ncomms5186

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