Coordination Funds

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Cells of multicellular organisms are permanently exposed to stress resulting from mechanical forces. Organismal health and protein homeostasis (proteostasis) depend in this situation on the adaptation of protein folding and degradation systems, which handle force-unfolded and damaged proteins. To elucidate mechanical stress protection, the research unit has implemented a highly interdisciplinary approach that integrates mechano- and cell biology, kidney, muscle and exercise physiology, molecular immunology, and worm and mouse genetics. In targeted studies and through unbiased transcriptomic and proteomic analysis mechano-protective mechanisms were uncovered in isolated cells and tissues, genetically tractable model organisms, and human subjects. Our work led to the identification of mechano-sensitive client proteins, central protection factors, and key regulatory components. Involved kinase and phosphatase dependent signalling networks were elucidated and reversible phosphorylation events relevant for mechano-protection were defined. These findings will direct the further analysis of proteostasis systems essential for mechanical stress protection and their force-dependent regulation through biochemical, cell biological, biophysical, proteomic and genetic methods. A focus for the second funding period will lie on the characterization of identified mechano-protection systems and signalling pathways across different tissues and organisms. The proposed work will reveal fundamental principles of mechanical stress protection in multicellular organisms and establish their relevance for human physiology and pathophysiology.