Research

No life without proteases. The new RTG-PRO places this class of enzymes at the center of its activities; and from this angle it gains a fresh look at inflammation and infection. The consortium’s focus is on precision proteolysis, which is equally important for the homeostasis of pathogen and host, and for the relationship between the two. Our choice of protease systems for study was guided by their importance for our understanding of the life processes, unsolved medical problems, and the degree of innovation. The selection will enable us to capture these processes in a theoretical concept of two orthogonal dimensions: resistance and resilience in the host organism, virulence/ immune evasion and fitness in the pathogen. Examples of virulence- and immune evasion factors are extracellular serine proteases of Gram-positive bacteria and CE-clan4 proteases produced by Gram-negative species. Host cell resilience and bacterial fitness are both vitally dependent on the maintenance of protein homeostasis through protein quality control. This is the main task of the host’s ubiquitin-proteasome system (UPS) and its bacterial counterpart, the Clp5 machinery. Endo/lysosomal proteases complete the picture, encompassing host resistance factors as well as the causative agents of severe endogenous inflammation and tissue destruction. The latter are typical of acute pancreatitis, which is triggered by the aberrant activation of trypsin. Molecular analyses of the sequence – structure – function relationships of the enzyme systems are another pillar of the research program. The consortium will apply state of the art proteomic, genetic, biochemical, and bioengineering approaches to reveal the proteases’ substrate spectrum and aim to distinguish physiological from pathological proteolysis. In the interest of optimal doctoral training, RTG-PRO balances focus and coherence with the necessary breadth of topics.