SFB 877:  Proteolysis as a Regulatory Event in Pathophysiology

Proteins are essential cellular building blocks with many structural and regulatory functions. Protein modifications are important physiologic regulatory elements and can be involved in the development of diseases such as inflammation, neurodegeneration and cancer. The CRC877 analyzes intra- and intercellular signal transduction pathways, which include a special form of protein modification, namely the cleavage of proteins. While most covalent modifications of proteins are reversible within fractions of seconds, cleavage of proteins is virtually irreversible and is therefore of unique but so far not thoroughly understood importance. Cells need hours to resynthesize cleaved proteins and many short-lived cells such as neutrophils will even not be able to do so. The CRC analyzes such protein cleavage reactions and developed the hypothesis that these are master switches of cellular communications, which are dysfunctional during the development of diseases. Results from the first and second funding period impressively corroborate this hypothesis. In the last funding period our consortium and the integrated research training group want to study how an understanding of proteolytic principles can be used translationally. The final goal of our initiative is to further develop strategies for novel therapeutic concepts in the treatment of inflammatory and neurodegenerative diseases and cancer.

DFG Programme Collaborative Research Centres

• A01 - Analysis of the role of the shedding protease ADAM 17 in vivo (Project Heads Chalaris, Athena ;  Rose-John, Stefan )
• A02 - Mechanisms of ADAM 17 activation in the context of IL-6R biology (Project Head Scheller, Jürgen )
• A03 - Insights into the cell biology and modulation of ADAM10 (Project Head Saftig, Paul )
• A04 - The cell membrane as regulatory element of transmembrane protease function (Project Head Reiss, Karina )
• A05 - Molecular mechanisms and functional consequences of ADAM protease activation induced by extracellular NAD or ATP (Project Head Koch-Nolte, Friedrich )
• A06 - Structure-function analysis of the extracellular part of ADAM 17 (Project Head Grötzinger, Joachim )
• A07 - Mechanism and implications of NKG2D ligand shedding (Project Head Kabelitz, Dieter )
• A09 - Regulation of meprin metalloproteases in inflammation and fibrosis (Project Head Becker-Pauly, Christoph )
• A10 - Role of proteolysis in interleukin-11 signaling (Project Head Garbers, Christoph )
• A11 - Mechanism of Factor XII-associated Hereditary Angioedema (Project Head Renné, Thomas )
• A12 - Therapeutic potential of proteolytically generated prion protein fragments to treat dementia (Project Heads Glatzel, Markus ;  Saftig, Paul )
• A13 - Structural and functional properties of meprin metalloproteases with regard to cell signaling (Project Head Arnold, Philipp )
• A14 - Proteolytic generation of the soluble interleukin-6 receptor in vivo (Project Heads Garbers, Christoph ;  Rose-John, Stefan )
• A15 - Functional role of meprin β in Alzheimer’s disease (Project Heads Becker-Pauly, Christoph ;  Pietrzik, Claus Ulrich )
• B01 - Role of ubiquitination and proteolysis in the regulation of pro- and anti-apoptotic TNF-R1 signaling (Project Head Schütze, Stefan )
• B02 - Proteolysis in the regulation of non-apoptotic cell death (Project Heads Adam, Dieter ;  Schütze, Stefan )
• B03 - Role of site-1 and site-2 protease for lysosomal homeostasis (Project Heads Braulke, Thomas ;  Pohl, Sandra )
• B04 - Proteolysis-dependent post-translational modifications in control of the death factor CD95L (Project Head Janßen, Ottmar )
• B06 - The role of mast cell-restricted transmembrane tryptase y (TMTy) in inflammation (Project Heads Bulfone-Paus, Silvia ;  Orinska, Zane )
• B07 - Characterization of the in vivo functions of Signal-peptide-peptidase-like 2 intramembrane proteases (Project Heads Saftig, Paul ;  Schröder, Bernd )
• B08 - Determinants of voltage-gated cation channels as substrates for regulated proteolysis (Project Heads Saftig, Paul ;  Schwake, Michael )
• B09 - Role of ORMDL proteins for ER stress, autophagy, protein degradation and intestinal homeostasis (Project Heads Rosenstiel, Ph.D., Philip Caspar ;  Schreiber, Stefan )
• B11 - The role of lysosomal cathepsins in α-synuclein metabolism and Parkinson’s disease (Project Head Zunke, Friederike )
• B12 - The role of microtubule detyrosination in dendritic structure and function (Project Head Mikhaylova, Marina )
• B13 - Regulation of matrix metalloprotease activity during proteolytic invasion of human macrophages (Project Head Linder, Stefan )
• B14 - Cathepsin B in the development of Focal Segmental Glomerulosclerosis (Project Head Theilig, Franziska )
• B15 - Proteolytic modulation of intestinal CD4 T helper cell function and immune homeostasis (Project Head Scheffold, Alexander )
• MGK - Integrated Research Training Group (Project Heads Becker-Pauly, Christoph ;  Grötzinger, Joachim ;  Leippe, Matthias ;  Pohl, Sandra )
• Z01 - Central Tasks (Project Head Rose-John, Stefan )
• Z02 - Mass Spectrometry based proteomics for the analysis of proteolytic events (Project Heads Janßen, Ottmar ;  Leippe, Matthias ;  Tholey, Andreas )
• Z03 - Proteases and proteolysis followed by microscopy (Project Heads Grötzinger, Joachim ;  Saftig, Paul )

Applicant Institution Christian-Albrechts-Universität zu Kiel

Participating University Johannes Gutenberg-Universität Mainz; Universität Hamburg

Spokesperson Professor Dr. Stefan Rose-John