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Mol. Cell. Biol. doi:10.1128/MCB.01567-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Deubiquitylating Enzyme UBP64 Controls Cell Fate Through Stabilization of the Transcriptional Repressor Tramtrack

Department of Biochemistry, Centre for Biomedical Genetics, Proteomics Center, Department of Cardiology, Erasmus University Medical Center, P.O. Box 1738, 2040 CA Rotterdam, The Netherlands, MRC Laboratory of Molecular Biology, Cambridge, UK

^* To whom correspondence should be addressed. Email: c.verrijzer{at}erasmusmc.nl.

	Abstract

Protein ubiquitylation plays a central role in multiple signal transduction pathways. However, the substrate specificity and potential developmental roles of deubiquitylating enzymes remain poorly understood. Here, we show that the Drosophila ubiquitin protease UBP64 controls cell fate in the developing eye. UBP64 represses neuronal cell fate but promotes formation of non-neuronal cone cells. Using a proteomics approach, we identified transcriptional repressor Tramtrack (TTK) as a primary UBP64 substrate. In common with TTK, reduced UBP64 levels leads to a loss of cone cells, and supernumerary photoreceptors and mechanosensory bristle cells. Previously, it was demonstrated that the blockade of neuronal cell fate was relieved by SINA-dependent ubiquitylation and degradation of TTK. We found that UBP64 counteracts SINA function by deubiquitylating TTK, leading to its stabilization and thereby promoting a non-neuronal cell fate. Mass spectrometric mapping revealed that SINA ubiquitylates multiple sites dispersed throughout TTK, which are duly deubiquitylated by UBP64. This observation suggests that both the E3 SINA and the UBP64 use a scanning mechanism to (de)ubiquitylate TTK. We conclude that the balance of TTK ubiquitylation by SINA and deubiquitylation by UBP64 constitutes a specific post-translational switch controlling cell fate.