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Molecular & Cellular Proteomics 7:2107-2122, 2008.
© 2008 by The American Society for Biochemistry and Molecular Biology, Inc.

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Research

The Ubiquitin-Proteasome System Is a Key Component of the SUMO-2/3 Cycle^*,S

Joost Schimmel^,, Katja M. Larsen^,¶, Ivan Matic^,||, Martijn van Hagen, Jürgen Cox^||, Matthias Mann^||, Jens S. Andersen^¶,** and Alfred C. O. Vertegaal^,

From the Department of Molecular Cell Biology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands, ^¶ Center for Experimental BioInformatics (CEBI), Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, DK-5230, Odense M, Denmark, and ^|| Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Am Klopferspitz 18, D-82152 Martinsried, Germany

Many proteins are regulated by a variety of post-translational modifications, and orchestration of these modifications is frequently required for full control of activity. Currently little is known about the combinatorial activity of different post-translational modifications. Here we show that extensive cross-talk exists between sumoylation and ubiquitination. We found that a subset of SUMO-2-conjugated proteins is subsequently ubiquitinated and degraded by the proteasome. In a screen for preferential SUMO-1 or SUMO-2 target proteins, we found that ubiquitin accumulated in purified SUMO-2 conjugates but not in SUMO-1 conjugates. Upon inhibition of the proteasome, the amount of ubiquitin in purified SUMO-2 conjugates increased. In addition, we found that endogenous SUMO-2/3 conjugates, but not endogenous SUMO-1 conjugates, accumulated in response to proteasome inhibitors. Quantitative proteomics experiments enabled the identification of 73 SUMO-2-conjugated proteins that accumulated in cells treated with proteasome inhibitors. Cross-talk between SUMO-2/3 and the ubiquitin-proteasome system controls many target proteins that regulate all aspects of nucleic acid metabolism. Surprisingly the relative abundance of 40 SUMO-2-conjugated proteins was reduced by proteasome inhibitors possibly because of a lack of recycled SUMO-2. We conclude that SUMO-2/3 conjugation and the ubiquitin-proteasome system are tightly integrated and act in a cooperative manner.

To whom correspondence may be addressed: Dept. of Molecular Cell Biology, Leiden University Medical Center, Postal zone S1-P, P. O. box 9600, 2300 RC Leiden, the Netherlands. Tel.: 31-71-5269621; Fax: 31-71-5268270; E-mail: vertegaal{at}lumc.nl

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