Untersuchungen der Ubiquitin-vermittelten Regulation von Apoptose in Drosophila - Ubiquitin-mediated regulation of apoptosis

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Activation of caspases, which execute the cell death programme, is an event that has to be tightly regulated. Members of the inhibitor of apoptosis (IAP) protein family ensure cell survival by blocking caspase activity. While it is generally believed that IAPs inhibit caspases due to a steric blockade, recent data from Drosophila indicate that IAP-mediated inactivation of caspases requires ubiquitin-conjugation. However, little is known regarding the molecular mechanism underlying ubiquitin-mediated inhibition of caspases. Thus, using Drosophila melanogaster as a model system, I propose a strategy to investigate ubiquitin-mediated regulation of caspases: I will examine the consequence of ubiquitylation of Dronc, a key initiator caspase in Drosophila that is poly-ubiquitylated and inactivated by DIAP1. I will determine the type and position of ubiquitin modification made. Non-ubiquitylatable Dronc-mutants will be generated and analysed in comparison to wild-type Dronc, regarding Dronc¿s catalytic activity, subcellular localization and ability to bind to protein partners. In parallel, I will elucidate how DIAP1¿s E3 ubiquitin-protein ligase activity is regulated. In particular, I will focus on the role of E2s, UEVs and E3 ligases in contributing to DIAP1¿s E3 activity. Together, these studies are likely to shed light into how RING-bearing IAPs keep caspases in abeyance and hence block apoptosis.