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

关于不同泛素（Ub）家族（UbF）蛋白（所谓UbF网络的组成部分）之间相互作用的出版物在该项目的过去应用期间已显着增加。很明显，例如Ub，Nedd 8和SUMO途径是不分离的。相反，在细胞周期调控、DNA修复、发育和信号转导等重要的细胞过程中，存在着许多与它们发生交叉作用的例子。在该项目的第一个应用阶段，我们专注于COP 9信号体（CSN）介导的去卷曲化的表征。我们发现，从人红细胞中纯化的CSN的deneddylation受到磷酸化的复合物。我们发现了CSN与去乙酰化酶1（DEN 1）的物理相互作用。我们的数据表明，CSN触发核定位以及降解的Ub蛋白酶体系统（UPS）的DEN 1。此外，我们开始产生条件性Csn 5D 151 N敲入和条件性Usp 15敲除小鼠品系。SPP 1365/2的下一阶段的主要目标是阐明CSN的去泛素化和去泛素化活性的生物学功能。我们将继续研究磷酸化和底物结合对CSN介导的去eddylation的影响。我们期望从条件Csn 5D 151 N敲入和Usp 15敲除小鼠品系的表征中了解生物学功能。

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.