Caspases are cysteine proteases that have been initially and extensively studied as the executioner of the end-point (cellular death) of apoptosis and also pyroptosis. Caspases (as an active enzyme or a scaffolding protein) also decisively control the release of intercellular mediators by interfering with different cellular signalling complexes such as ripoptosome, faddosome, or inflammasome. Here we aim to explore how and why caspases associate different signalling compartments and which substrates are targeted by caspases upon activation. Our longstanding goal is to identify new caspase targets that are processed by caspases and impact on cellular responses including different modes of cell death and cytokine secretion. Complementary analyses in newly engineered mouse models aims to discover the physiologic roles of caspases in cancer and infectious diseases. One long-term objective of this project is to establish cellular and animal systems either lacking the identified caspase substrates or harbour mutations in the peptide sequence required for caspase-mediated processing (CRISPR/Cas9 gene-editing). The impact of the identified factors and their processing on cancer and immunity will be investigated in vitro and in vivo in disease models.

The members of the inhibitor of apoptosis protein (IAP) family including cIAP1, cIAP2 and XIAP have been initially described as caspase inhibitors that are highly expressed in tumour cells and promote cancer progression, presumably, by inhibiting apoptosis. Accumulating recent evidence showed that IAPs are ubiquitin ligases that control inflammation by modifying a number of signalling moieties such as RIPK1 and RIPK2. These data provided an expanded view of IAPs in the networks including multiple death programs (apoptosis, necroptosis and pyroptosis) and inflammatory signalling. Accordingly, the elevated expression of IAPs in cancer may not solely counteract cell death but can also contribute to tumour-associated inflammation required for cancer progression. The ubiquitin ligase activity of IAPs is crucial for their signalling function. We aim to characterise targets of IAPs in tumour cells and cells infected with bacterial pathogens. We are using cell-free ubiquitylation systems and cell culture system in order to validate our findings. New mouse models expressing enzymatically inactive IAPs will help us to monitor the physiologic relevance of our finding.  Furthermore, in collaboration with industrial partners we are validating the use of novel IAP inhibitors in cancer and infectious diseases.