Regulation of ubiquitin-binding proteins by monoubiquitination (original) (raw)

Nature Cell Biology volume 8, pages 163–169 (2006)Cite this article

Abstract

Proteins containing ubiquitin-binding domains (UBDs) interact with ubiquitinated targets and regulate diverse biological processes, including endocytosis, signal transduction, transcription and DNA repair1,2,3. Many of the UBD-containing proteins are also themselves monoubiquitinated, but the functional role and the mechanisms that underlie this modification are less well understood. Here, we demonstrate that monoubiquitination of the endocytic proteins Sts1, Sts2, Eps15 and Hrs results in intramolecular interactions between ubiquitin and their UBDs, thereby preventing them from binding in trans to ubiquitinated targets. Permanent monoubiquitination of these proteins, mimicked by the fusion of ubiquitin to their carboxyl termini, impairs their ability to regulate trafficking of ubiquitinated receptors. Moreover, we mapped the in vivo monoubiquitination site in Sts2 and demonstrated that its mutation enhances the Sts2-mediated effects of epidermal-growth-factor-receptor downregulation. We propose that monoubiquitination of ubiquitin-binding proteins inhibits their capacity to bind to and control the functions of ubiquitinated targets in vivo.

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Acknowledgements

We thank S. Urbe, S. Polo and P.P. DiFiore for discussions and help with these studies, as well as W. Mueller-Esterl and members of the Dikic laboratory for constructive comments and critical reading of the manuscript. We are very thankful to M. Offterdinger and P. Bastiaens for help with the FRET experiments and to I. Konrad for excellent technical assistance. This work was supported by grants from the Deutsche Forschungsgemeinschaft (DI 931/1-1) and Boehringer Ingelheim Fonds (to I.D.) and the Danish National Research Foundation (to M.M.). C.R. receives a postdoctoral fellowship from the Norwegian Cancer Society.

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Authors and Affiliations

  1. Institute for Biochemistry II, Goethe University Medical School, Theodor-Stern-Kai 7, Frankfurt, 60590, Germany
    Daniela Hoeller, Nicola Crosetto, Ritva Tikkanen, Sebastian Wagner & Ivan Dikic
  2. Center for Experimental Bioinformatics, University of Southern Denmark-Odense, Campusvej 55, Odense, 5230, Denmark
    Blagoy Blagoev & Matthias Mann
  3. Department of Biochemistry, The Norwegian Radium Hospital, Montebello, Oslo, N-0310, Norway
    Camilla Raiborg & Harald Stenmark
  4. Ludwig Institute for Cancer Research, Box 595 Uppsala, Uppsala, 75124, Sweden
    Katarzyna Kowanetz
  5. Groningen Bioinformatics Centre, University of Groningen, Haren, 9751 NN, The Netherlands
    Rainer Breitling
  6. Department of Proteomics and Signal Transduction, MPI, Am Klopferspitz 18, Martinsried, 82152, Germany
    Matthias Mann

Authors

  1. Daniela Hoeller
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  2. Nicola Crosetto
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  3. Blagoy Blagoev
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  4. Camilla Raiborg
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  5. Ritva Tikkanen
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  6. Sebastian Wagner
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  7. Katarzyna Kowanetz
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  8. Rainer Breitling
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  9. Matthias Mann
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  10. Harald Stenmark
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  11. Ivan Dikic
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Correspondence toIvan Dikic.

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Hoeller, D., Crosetto, N., Blagoev, B. et al. Regulation of ubiquitin-binding proteins by monoubiquitination.Nat Cell Biol 8, 163–169 (2006). https://doi.org/10.1038/ncb1354

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