Ubiquitin abhängige Proteolyse eines Substrates des Zellkerns (Ubiquitin dependent proteolysis of a nuclear substrate)

我们已经确定了位于内质网膜上的泛素系统的成分，它们似乎是降解膜结合和内质网膜蛋白降解底物的关键酶。尽管它们在内质网降解中发挥作用，但这些成分参与了转录抑制因子Matalpha2的周转。我们详细研究了这种底物的降解，并提供了证据，证明了蛋白质从细胞核输出与通过泛素-蛋白酶体途径降解之间的新的、意想不到的联系。这种转录调节因子的快速蛋白质分解依赖于一条穿过细胞核的通道，并需要一个依赖于Cse1p的功能蛋白质输出途径。有趣的是，Mat-Alpha 2必须通过这种出口途径离开细胞核，才能迅速降解。然而，通过不同的途径运输会导致缓慢的周转。我们未来的目标，也是这项提议的主题，是确定这一出口途径中涉及的组件，并从机械上澄清核出口与泛素蛋白酶体系统之间的联系。

We have identified components of the ubiquitin system localized at the ER-membrane which seem to be key enzymes for the degradation of membrane-bound and ER-lumenal proteolytic substrates. Despite their function in ER-degradation, these components are involved in the turnover of the transcriptional repressor Matalpha 2. We have investigated the degradation of this substrate in detail and provide evidence for a new and unexpected link between protein export from the nucleus and degradation via the ubiquitin-proteasome pathway. Rapid proteolysis of this transcriptional regulator relies on a passage through the nucleus, and requires a functional Cse1p dependent protein export pathway. Interestingly, Mat-alpha 2 has to leave the nucleus specifically via this export route to be degraded rapidly. Transport through a different pathway however, results in slow turnover. Our future goals, which are subject of this proposal, are the identification of the components involved in this export pathway and clarify mechanistically the link between nuclear export and the ubiquitin proteasome system.