Proteolysis: The Most Important and Ubiquitous Post Translational Modification that Regulates Biology, Life and Death

We are at the end of the beginning in understanding protease biology…

Every protein in all forms of life undergoes proteolysis, making proteolysis the most important post-translational modification of proteins in the proteome. Rather than being primarily involved in degradation, proteases have equally or more important roles as efficient processing enzymes of many bioactive mediators such as cytokines, growth factor binding proteins, chemokines, their receptors and specific protein anchors for these molecules. Limited and specific processing of bioactive mediators can lead to profound alterations in cell behaviour resulting in shedding of cell surface molecules, mobilization of proteins in different cellular compartments, activation and inactivation of signalling molecules - sometimes converting activity from agonists to antagonists, cell death, and for certain proteins, exposing cryptic biologically active epitopes and neoproteins from precursor molecules of unrelated function. Plants, microorganisms and viruses similarly utilize proteolysis for essential functions and in pathogenic species often utilize proteases as virulence factors. In addition proteolytic activation or inactivation of other proteases and inhibitors links many proteases in a proteome to form an interconnected ‘Protease Web’, the net activity of which moulds the proteome, dynamically regulating homeostatic, physiological and host defence responses. Hence, dramatically increased knowledge of the physiological functions of proteases is required in order to then understand the roles of proteases and inhibitors in pathology and so devise rational targeting strategies for therapeutic intervention with new generations of antiproteolytic inhibitor drugs. Implicit in these goals is the discovery of protease substrates and their binding partners in vivo, and to image their activity in living systems. These diverse and important functions potentially explain the paradoxical positive and negative effects of proteases in diseases such as cancer, arthritis, and neurodegeneration that led to the realization that whereas some proteases are important drug targets, many others are anti-targets, having beneficial host protective roles. Hence, the results of some disappointing protease inhibitor drug trials can be so understood, while at the same time sharpening the goals for effective new drug treatments of disease based on scrupulous target validation, identification of antitargets and countertargets and innovative new chemistries.

On this backdrop, the 2010 Proteolytic Enzymes and Inhibitors Gordon Research Conference will present the most recent and innovative research in proteases and their inhibitors in a multidisciplinary manner and in a new program format. Moreover, many new and establishing investigators have been invited to present their work alongside those from established laboratories. Several short talks are reserved for trainees that will be selected from the poster abstracts and a few full speaker slots have been held for the latest breaking stories. Together with the recreational and culinary activities possible at the 5 Star Il Ciocco Hotel and Resort in Northern Tuscany, I hope this ensures a vibrant, interactive, enthusiastic and fun meeting that features the most innovative protease research of our time.

In Italy 2010, the processing functions of proteases will be emphasised with respect to interconnections of the proteases with signalling networks that alter overall cell behaviour. The future outlook and potential for anti-proteolytic drugs will be discussed throughout the meeting in relation to new discoveries on the positive and negative roles of proteases in disease. With many aspects of the structural biology of proteases and inhibitors now well established, it is time to turn to innovative methods of studying and resolving the dynamic nature of proteases in catalysis and in vivo by new imaging techniques. Embracement of proteomics by the protease field has, in general, been slow due to significant technical challenges. Hence, establishing the roles of proteases by system-wide level investigations remains in its infancy, but will be a hot topic of discussion now that several approaches are now robust enough to profile substrate processing in tissues in a multiplex manner and to image proteolytic activity in mouse models of disease. It is hoped that these discussions and presentations will further nucleate the field to research the roles of proteinases and their impact on the substrate degradome in physiological processes at a system-wide level as an essential prerequisite to understanding their role in pathology.

Dr Klaudia Brix and I invite protease researchers to gather in the Tuscan sunshine in the spring of 2010 at the first Proteolytic Enzymes and Inhibitors GRC to be held at Il Ciocco Hotel and Resort, Lucca (Barga), Toscona, Italia.

Chris Overall
Chair, 2010 Proteolytic Enzymes and Inhibitors GRC