Ubiquitin networks in cell death regulation and non-apoptotic signalling

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The posttranslational modification with ubiquitin (Ub), a process referred to as ubiquitylation, controls important aspects of cell death and survival. Ub can be attached to pro- and anti-apoptotic proteins as a single moiety or in the form of polymeric chains in which successive ubiquitin molecules are connected through specific isopeptide bonds. Reminiscent of a code, the various ubiquitin modifications adopt distinct conformations and lead to different outcomes in cells. To prevent ubiquitylation from being constitutively on, modifications are reversed by de-ubiquitylating enzymes (DUB) that cleave off the Ub adduct. While the consequence of Ub-attachment is intensely studied, little is known with regards to the effects of deconjugating enzymes that remove the Ub-adduct. The aim of the proposed programme is to unravel how the ubiquitin-signal is conjugated and edited to modulate cellular processes that are required during normal development and tissue homeostasis. We will use a series of interlocking genetic and biochemical approaches to identify and characterise DUBs that regulate caspase-mediated cell death and non-apoptotic signalling. In a pilot study we identified several DUBs that, when removed, suppress cell death in vivo. Here we propose to investigate the physiological role and molecular mechanism of five of these DUBs. Particularly, we will assess whether they function as integral and evolutionarily conserved components of the tissue repair process. Importantly, a growing body of evidence indicate that caspase-mediated signalling generates the release of signals that communicate with the cellular environment to coordinate compensatory proliferation, tissue regeneration and wound healing. Hence, we will also assess whether loss of the identified DUBs also affects caspase activation required for adaptation to tissue stress. Taken together, we propose to investigate the dynamics and specificity of Ub networks and study how Ub conjugation and deconjugation impact on signaling outcomes. Unravelling how DUBs regulate cell death and non-apoptotic signalling is critically important as these processes play fundamental physiological roles in animal development and tissue homeostasis.