Regulation of small GTPase signalling networks and chaperone-assisted selective autophagy through mechanical forces in leukocytes and cardiomyocytes

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Mechanical stress acts on immune cells, which exit from the vasculature, which crawl on endothelial layers in the vascular lumen, or which are confronted with mechanical barriers in at tissue interfaces or in interstitial spaces. Our labs specialize in the construction of biophysical sensors of protein functions and dynamics, as well as the biochemical and functional elucidation of intracellular communication pathways, which control force transduction in leukocyte adhesion and migration. Using genetic ablation in the mouse, we identified the cytohesin family of guanine nucleotide exchange factors (GEFs) for ADP-ribosylation factor (Arf)-GTPases, as regulators of integrin-mediated cell adhesion in leukocytes. Tissue specific genetic ablations of cytohesin-2 in the immune system and in cardiomyocytes led to altered adhesion signalling and migration in so-called dendritic cells, and to heart fibrosis and premature death in mice, respectively. Furthermore, we showed earlier in collaboration with the Höhfeld lab that the BAG3 chaperone machinery contributes to mechanotransduction not only in muscle cells, but also in immune cells. Recent evidence suggests that cytohesin-dependent functions and Rap1-GTPase signalling, a fundamental regulator of integrin activation, converge on RhoA and BAG3 in immune cells and in heart muscle cells. In this project, we will therefore elucidate the role of Arf-GEF/Arf-GTPase dependent signalling mechanism in the control of mechanical stress protection. We will utilize genetics, biochemical methods and dynamic visualization of local subcellular GTPase signalling, using state-of-the-art biosensor technologies to elucidate stress signalling via the cytohesin/Rap1/RhoA/BAG3 axes. Our work will establish force-dependent signalling networks required for mechanical stress protection in leukocytes and cardiomyocytes.