Mechanisms and Regulation of Rhomboid Intramembrane Proteolysis

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During evolution, species acquired new genes through gene duplication as well as through modifications. Obviously, there are substantial evolutionary differences between kingdoms of life such as bacteria, archaea, fungi, plantae and animals. Despite these diversities, it is remarkable that some proteins were conserved in all kingdoms throughout evolution and can be found in mammals as well as in the common bacteria Escherichia coli. Such conservation of proteins implies that they carry fundamental functions, i.e., they are required to ensure normal functioning of the organism throughout all types of life. Such conserved proteins comprises the rhomboid proteases, which we are investigating. Rhomboid proteases are bound in cell membranes and control the release of signaling molecules, which are often essential for the communication between cells. The bacterial rhomboid proteases are well studied and we even know the exact structure of bacterial rhomboid proteins. But despite their conservation up to animals, there are only a few publications describing first studies of their potential functions in mammals. We want to advance the knowledge on mammalian rhomboid proteases since we are convinced that they carry essential biological functions in mammals. To achieve our aims, we follow three research projects: 1) To unravel the function of a rhomboid protease, it is helpful to know the substrate that is processed by the protease. We have recently identified a novel substrate for one rhomboid protease, rhomboid-like-4. With this novel substrate, we will be able to investigate how the enzyme recognizes the substrate and how rhomboid enzymatic activity is regulated. 2) Rhomboid-like-4 and its new substrate both occur in kidney and lung. We hypothesize that rhomboid-like-4 controls the levels of substrates at the cell surface and therefore impacts on the cell-cell communication in kidney and/or lung. We will further investigate with which proteins this rhomboid protease interacts inside the cell. 3) Our third project investigates rhomboid protease-1, a rhomboid about which very little knowledge is available. We are the first research group to experimentally analyze this rhomboid protease: We determined that rhomboid-like-1 occurs in neurons and we are investigating a mouse model with a deletion in this gene, which will tell us about its physiological functions. In summary, the trainees in my laboratory are performing basic biochemical research from the very first steps to investigate this family of remarkable enzymes in mammalian system and to shed light on their physiological functions.