The ubiquitin-proteasome system is a key component of the SUMO-2/3 cycle.
Mol Cell Proteomics. 2008 Jun 18. [Epub ahead of print]
Schimmel J, Larsen KM, Matic I, van Hagen M, Cox J, Mann M, Andersen JS, Vertegaal AC.
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 crosstalk 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. Crosstalk 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 due to 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.