Letter abstract
Nature Cell Biology 8, 163 - 169 (2006)
Published online: 22 January 2006 | doi:10.1038/ncb1354
Regulation of ubiquitin-binding proteins by monoubiquitination
Daniela Hoeller1, Nicola Crosetto1, Blagoy Blagoev2, Camilla Raiborg3, Ritva Tikkanen1, Sebastian Wagner1, Katarzyna Kowanetz4, Rainer Breitling5, Matthias Mann2,6, Harald Stenmark3 & Ivan Dikic1
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.
- Institute for Biochemistry II, Goethe University Medical School, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
- Center for Experimental Bioinformatics, University of Southern Denmark-Odense, Campusvej 55, 5230 Odense, Denmark.
- Department of Biochemistry, The Norwegian Radium Hospital, Montebello, N-0310 Oslo, Norway.
- Ludwig Institute for Cancer Research, Box 595 Uppsala, 75124 Uppsala, Sweden.
- Groningen Bioinformatics Centre, University of Groningen, 9751 NN Haren, The Netherlands.
- Department of Proteomics and Signal Transduction, MPI, Am Klopferspitz 18, 82152 Martinsried, Germany.
Correspondence to: Ivan Dikic1 e-mail: ivan.dikic@biochem2.de
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