Prof. Dr. Pitter Huesgen

Proteases fulfill essential functions in maintaining protein homeostasis and cellular signaling. Degradative proteolysis not only removes non-functional and obsolete proteins but also exerts regulatory control by targeted degradation of selected proteins. In addition, site-specific proteolytic processing constitutes an irreversible post-translational modification that can change substrate protein location, interaction, and function. Deregulated proteolysis is a major cause of human disease and in many cases proteases are considered as attractive drug targets. However, incomplete knowledge of their physiological substrates and interactions hampers understanding of beneficial or protective functions and thus prediction of undesired side effects.

Our research: We study proteolysis on a system-wide scale. Which proteins are proteolytically processed or degraded, what are the functional consequences, how is substrate recognition and corresponding proteolytic enzyme(s) regulated, how do these processes interact with other signaling pathways? To address these questions, we combine system-wide profiling of proteolytic processing and degradation with targeted analysis of the substrate repertoires and regulation of selected proteolytic enzymes.

Our goals: We strive to understand proteolytic networks regulating biological signaling in selected fundamental biological processes, such as regulated cell death and in specific disease models. We anticipate that a deeper understanding of these networks will allow us to identify new opportunities for specific detection and therapy of various human diseases.

Our successes: We have developed mass spectrometry-based methods that enable determination of proteolytic cleavages in complex biological systems, including microscale samples. In pioneering collaborative work at CECAD, we could show that proteolytically derived proteoforms exist at the renal filtration barrier, and that the abundance of these proteoforms is altered upon injury or disease both in vitro and in vivo.

Our methods/techniques: We specialize in the development and application of quantitative mass spectrometry-based methods, particularly degradomics methods for sensitive detection of protein termini (HUNTER, TAILS, CTAILS) and protease specificity (PICS). We also develop new tools such as specific digestion proteases for bottom-up proteomics (LysargiNase, legumain) and multimodal mass spectrometry imaging of elements and biomolecules in biological tissues (LA-ICP-MSI, MALDI-MSI).