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

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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.