Regulation of intracellular HTRA1 protease

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The HtrA family represents a unique class of oligomeric serine proteases. Their defining features are the combination of a catalytic domain with C-terminal PDZ domains and that the switch between the inactive and active conformations is reversible. Even though human HTRA1 is implicated in several severe pathologies such as cancer, age-related macular degeneration, Alzheimer's disease, arthritis and familial ischemic cerebral small-vessel disease, close to nothing is known about how this protease is regulated in the cell. The main objective of this proposal is therefore to identify and analyse cellular factors involved in regulating the activity of cytoplasmic HTRA1 and to characterise the corresponding physiologic consequences. To identify the underlying molecular mechanisms, protein complexes between HTRA1 and its regulatory ligands as well as posttranslational modifications will be studied. These data will allow us to address the important question in which cellular processes the regulation of HTRA1 is of particular importance. Correspondingly, these studies are expected to reveal deeper insights into the roles of this widely conserved protease in protein homeostasis of human cells.