Proteolysis as a Regulatory Event in Pathophysiology

Sonderforschungsbereich 877

An der Christian-Albrechts-Universität zu Kiel

First Funding Period

Research Area B

Schema Projekt B

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Intracellular Proteolysis: From Cell Biology to Disease
(overview)

 B1 (visit project website)
Schütze (Institut für Immunologie, UKSH Kiel):
Role of ubiquitinylation and proteolysis in the regulation of pro- and anti-apoptotic TNF-RI signaling
(Fachrichtung Molekulare Immunologie)
 B2 (visit project website)
Adam / Schütze (Institut für Immunologie, UKSH Kiel):
Proteolysis in the regulation of caspase-independent programmed cell death (Fachrichtung Molekulare Immunologie
 B3 (visit project website)
Pohl / Braulke (Abteilung Biochemie, Kinderklinik, UKE Hamburg):
Proteolysis-mediated regulation of mannose 6-phosphate-dependent transport of lysosomal enzymes
(Fachrichtung Biochemie)
 B4 (visit project website)
Janßen (Institut für Immunologie, CAU Kiel):
Proteolysis-dependent post-translational modifications in control of the death factor CD95L (Fachrichtung Molekulare Immunologie)
 B7 (visit project website)
Saftig (Biochemisches Institut, CAU Kiel):
Characterization of the in vivo functions of signal-peptide-peptidase-like 2-a/b (SPPL2-a/b) in mouse models
(Fachrichtung Biochemie)
 B8 (visit project website)
Schwake (Biochemisches Institut, CAU Kiel):
Determinants of voltage-gated cation channels as substrates for regulated proteolysis (Fachrichtung Biochemie)
 B9 (visit project website)
Rosenstiel / Schreiber (Institut für Klinische Molekularbiologie, UKSH Kiel):
Genetic variants in protein degradation pathways: from normal population variability to altered inflammatory responses in the intestinal tract (Fachrichtung Innere Medizin, Humangenetik)

 

Overview

Intracellular proteolytic processes are analyzed within Research Area B. The project of Schütze (B1) deals with the role of ubiquitin and the proteasome in the regulation of TNF signaling (B1). Proteolytic reactions involved in the regulation of caspaseindependent programmed cell death will be analyzed by the project of Adam / Schütze (B2). Posttranscriptional modifications, which include shedding of Fas ligand by ADAM10 and SPPL2A, are important for the activity of apoptotic pathways. This project is performed by Janßen (B4). The aim of the project Rosenstiel / Schreiber (B9) is to systematically describe natural variability in the genes involved in protein degradation and to investigate the association of SNPs in protein degradation pathway genes with inflammatory disorders. The in vivo functions of signalpeptidase- like 2A and 2B will be studied in mouse models by the group of Saftig (B7).

Voltage-gated calcium channels can be cleaved by proteases leading to the release of intracellular fragments, which can drive transcription. The group of Schwake (B8) will ask whether such a mechanism is also operative for other voltage-gated ion channels such as potassium channels.

The intracellular consequences of proteolyic reactions studied in Research Area B range from cytokine signaling to the induction of cell death. The pathophysiologic consequences of dysregulated proteolytic reactions are largely unknown. Such consequences will on the one hand be studied by the analysis of patient data and tissues. We expect additional insights into the involvement of proteases in intracellular signaling by the analysis of invertebrate models. On the other hand, pharmacogenetic analyses will help to understand the functional relevance of proteases in the development of chronic inflammatory diseases and cancer. For this strategy the group of Rosenstiel / Schreiber (B9) chose a pathway based approach, genome wide association studies and next generation sequencing in healthy subjects using the data generated in the PopGen project, in which blood from patients in Schleswig-Hostein is collected and patient DNA is sequenced.

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