Regulation of ubiquitin-binding proteins by monoubiquitination

Daniela Hoeller; Nicola Crosetto; Blagoy Blagoev; Camilla Raiborg; Ritva Tikkanen; Sebastian Wagner; Katarzyna Kowanetz; Rainer Breitling; Matthias Mann; Harald Stenmark; Ivan Dikic

doi:10.1038/ncb1354

Regulation of ubiquitin-binding proteins by monoubiquitination

Nat Cell Biol. 2006 Feb;8(2):163-9. doi: 10.1038/ncb1354. Epub 2006 Jan 22.

Authors

Daniela Hoeller¹, Nicola Crosetto, Blagoy Blagoev, Camilla Raiborg, Ritva Tikkanen, Sebastian Wagner, Katarzyna Kowanetz, Rainer Breitling, Matthias Mann, Harald Stenmark, Ivan Dikic

Affiliation

¹ Institute for Biochemistry II, Goethe University Medical School, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.

PMID: 16429130
DOI: 10.1038/ncb1354

Abstract

Proteins containing ubiquitin-binding domains (UBDs) interact with ubiquitinated targets and regulate diverse biological processes, including endocytosis, signal transduction, transcription and DNA repair. 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing
Amino Acid Sequence
Calcium-Binding Proteins / genetics
Calcium-Binding Proteins / metabolism
Carrier Proteins / genetics
Carrier Proteins / metabolism
Carrier Proteins / physiology*
Cell Line
Endosomal Sorting Complexes Required for Transport
Endosomes / metabolism
ErbB Receptors / metabolism
Fluorescence Resonance Energy Transfer
Green Fluorescent Proteins / genetics
HeLa Cells
Humans
Intracellular Signaling Peptides and Proteins
Lysine / genetics
Lysine / metabolism
Membrane Proteins
Models, Molecular
Molecular Sequence Data
Mutation / genetics
Phosphoproteins / genetics
Phosphoproteins / metabolism
Protein Binding
Protein Tyrosine Phosphatases
Recombinant Fusion Proteins / genetics
Recombinant Fusion Proteins / metabolism
Sequence Homology, Amino Acid
Transfection
Transferrin / metabolism
Ubiquitin / metabolism
Ubiquitin / physiology*

Substances

Adaptor Proteins, Signal Transducing
CLIP4 protein, human
Calcium-Binding Proteins
Carrier Proteins
Cyan Fluorescent Protein
EPS15 protein, human
Endosomal Sorting Complexes Required for Transport
Intracellular Signaling Peptides and Proteins
Membrane Proteins
Phosphoproteins
Recombinant Fusion Proteins
Transferrin
Ubiquitin
hepatocyte growth factor-regulated tyrosine kinase substrate
Green Fluorescent Proteins
ErbB Receptors
Protein Tyrosine Phosphatases
UBASH3B protein, human
Lysine