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

我们已经确定了位于ER膜的泛素系统的组成部分，这似乎是膜结合和ER内腔蛋白水解底物降解的关键酶。尽管它们在ER-降解中起作用，但这些组分参与转录抑制因子Matalpha 2的周转。我们已经详细研究了这种底物的降解，并为蛋白质从细胞核出口和通过泛素-蛋白酶体途径降解之间的新的和意想不到的联系提供了证据。这种转录调节因子的快速蛋白水解依赖于通过细胞核，并且需要功能性Cse 1 p依赖性蛋白输出途径。有趣的是，Mat-α 2必须通过这种输出途径离开细胞核才能迅速降解。然而，通过不同途径运输导致周转缓慢。我们未来的目标，这是本提案的主题，是识别参与这一出口途径的组件，并澄清机械核出口和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.