The Ubiquitin-Proteasome System is a Key Component of the Cellular SUMO-2/3 Cycle.

Tightly controlled degradation of many proteins by the ubiquitin-proteasome system regulates virtually all cellular processes. Aberrant protein turnover is linked to diseases such as cancer, Alzheimers disease and Parkinsons disease. Currently, 12 ubiquitin-like proteins have been identified including three SUMOs. We have recently uncovered a tight connection between SUMO-2 and the ubiquitin-proteasome system. We have identified a subset of SUMO-2 target proteins that are simultaneously ubiquitinated in a proteasome-inhibitor sensitive manner. Furthermore, we have found that SUMO-2 is ubiquitinated in vivo on lysine 32. Using quantitative proteomics, we have purified and identified 161 SUMO-2 conjugated proteins that are sensitive to proteasome inhibition. The objective of this project proposal is to study the functional consequences of this crosstalk between ubiquitin and SUMO-2 at the target protein level and to study the molecular machinery that mediates this crosstalk. This project should uncover the molecular details of the surprising crosstalk between the ubiquitin-proteasome system and SUMOs, which could reveal a new biochemical regulatory pathway and this could be employed to counteract disease associated aberrations.