The biological function of the COP9 signalosome-mediated deneddylation and deubiquitination

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Publications on the interplay between different ubiquitin (Ub) family (UbF) proteins, constituents of the so called UbF network, have been significantly increased during the past application period of the project. It became clear that for example Ub, Nedd8 and SUMO pathways are not separated. In contrary, there exist many examples for their cross-talks in essential cellular processes ranging from cell cycle control, DNA repair, development to signal transduction. In the first application period of the project we have focused on the characterization of COP9 signalosome (CSN)-mediated deneddylation. We found that deneddylation by purified CSN from human red blood cells was affected by phosphorylation of the complex. We discovered a physical interaction of the CSN with the deneddylating enzyme 1 (DEN1). Our data show that the CSN triggers nuclear localization as well as degradation by the Ub proteasome system (UPS) of DEN1. In addition, we started to generate a conditional Csn5D151N knockin and a conditional Usp15 knockout mouse strain. Main objective of the forthcoming period of SPP 1365/2 will be the elucidation of the biological functions of the deneddylating and deubiquitinating activities of the CSN. We will continue to investigate the impact of phosphorylation and substrate binding on the CSN-mediated deneddylation. Most insights into the biological functions we expect from the characterization of the conditional Csn5D151N knockin and Usp15 knockout mouse strains.