Determining the molecular mechanisms regulating lysosome damage and repair pathways

Lysosomes are ubiquitous membrane-bound organelles that release hydrolytic enzymes and hydrogen ions into the cytoplasm when ruptured. This can result in DNA damage, impeded degradation of lysosomal substrates, inflammation and neurodegenerative diseases. Understanding how cells respond to such stress and how the repair/removal pathways are regulated is paramount to controlling cellular and tissue homeostasis as well as developing future therapeutic strategies. A number of stimuli can induce lysosomal damage and rupture, including bacterial pathogens, viruses, silica crystals and lysosomotrophic agents (LLOMe). In addition, inducing lysosome damage in cancer cells with high levels of cathepsins is seen as a viable therapeutic option. However, there is a serious lack of knowledge regarding the mechanisms that sense damage, repair or remove lysosomes that are initiated when lysosomes are ruptured.

We will use a siRNA screen to identify key regulators of this process, with particular emphasis on potentially druggable targets. We will focus our efforts on kinases, phosphatases, de-ubiquitinases and membrane trafficking genes.

We hope to identify a number of genes that can be analysed in greater detail with particular focus on regulation of bacterial infection and lysosome-induced cancer cell death pathways.