Collaborative Research Centre 877

Proteolysis as a Regulatory Event in Pathophysiology

Christian-Albrechts-Universität zu Kiel

The general aim of the CRC877 has been to obtain a profound understanding of proteolytic processes in cellular regulation and signaling and to characterize the roles of proteolytic pathways in human pathophysiology. The nature of substrates de­fines the functions of proteases. Therefore, the identification of single enzymes, their substrates, inhibitors and other regulatory proteins, the so called "protease web", is crucial to understand complex molecular events responsible for pa­tho­phy­sio­lo­gi­cal conditions. Molecules such as cytokines and growth factors and processes like apoptosis, cellular barrier function, blood clotting, the ubiquitin proteasome system and autophagy have been implicated in the development of many if not all acute and chronic inflammatory or neurodegenerative diseases.

The process of proteolysis is irreversible, in contrast to other posttranslational modifications such as protein phos­pho­ry­la­ti­on, protein lipidation or protein methylation. Therefore, proteolysis represents an entirely different and presumably higher level of regulation than the other mentioned protein modifications. Furthermore, signaling via proteases is usually fast and thus is used by the organism for stress or danger responses during inflammatory states.

The goal of our CRC is to learn about the molecular mechanisms regulating extracellular, intramembrane and intracellular proteolytic steps in signaling cascades and to understand the conceptual differences between proteolytic steps and other fast and reversible signaling events such as phosphorylation, lipidation and methylation. We also address the emerging concept of intracellular proteolytic networks, which serves the communication between different proteolytic pathways. These networks become apparent when proteases are pharmacologically blocked or genetically ablated. In such a si­tu­a­tion, other proteases are seen to compensate for the loss of the lacking protease activity. The understanding of molecular mechanisms of protease activation or deactivation as well as the communication between proteases will not only help us to define pathophysiologic situations mediated by cytokines, growth factors, binding of neighboring cells and other regulatory networks but also contribute to define points of intervention for the development of novel therapeutic principles.