Mechanotransduction at podosomes
Final Report Abstract
In this project, we identified lymphocyte‐specific protein 1 (LSP1),as an important component of the cap that enables oscillatory contractility of podosomes that is required for mechanosensing. We could also show that LSP1 is crucial in macrophages to perform an actomyosin symmetry break, i.e. a cellular gradient in contractility, that allows polarized migration. LSP1 and the myosin hyperactivator supervillin are localized to different parts of the macrophage cell, as LSP1 has preferential binding ability for β‐actin over α‐actin, thus localizing to the β‐actin‐rich periphery and blocking access of supervillin to this region. These data also gave a detailed molecular explanation for the known LSP1‐ based defects in immune cell migration in diseases such as rheumatoid arthritis or neutrophil actin dysfunction (NAD), opening potentially new treatment options. We have also developed a Fiji‐based macro we termed “Poji”(podosome analysis by Fiji), which enables the analysis of a variety of cellular and podosome‐associated parameters, notably fluorescence intensity of podosome components in different optical planes, wich allows detailed analysis of podosome architecture and substructures. Poji is also able to analyse size and subcellular distribution of podosomes, as well as podosome‐ and invadopodia‐associated degradation of extracellular matrix. In a third line of research, we analysed molecular mechanisms of podosome contact with microtubule plus tips. We could show that the actin‐ and microtubule binding protein drebrin is a new component of the podosome cap. SiRNA‐mediated knockdown coupled with Poji and Trackmate analysis further showed that drebrin is also a positive regulator of contact duration between podosomes and microtubule plus tips. It is highly likely that the respective molecular mechanism involves drebrin at podosomes binding to the microtubule plus tip protein EB3. Accordingly, a dominant negative construct inhibiting this binding also drastically reduced podosomal F‐actin. http://www.hamburg.de/bwfg/10402246/immunzellen‐lassen‐ihre‐muskeln‐spielen
Publications
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(2017). Actin assembly mechanisms at a glance. J. Cell Sci. 130, 3427-3435
Rottner, K., Faix, J., Bogdan, S., Linder S., Kerkhoff, E.
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(2018). Clinical relevance of cytoskeleton associated proteins for ovarian cancer. J. Cancer Res. & Clin. Onc., 144(11):2195-2205
Schiewek. J., Schumacher, U., Lange, T., Wikman, H., Pantel, K., Mikhaylova, M., Kneussel, M., Linder, S., Schmalfeldt, B., Oliveira-Ferrer, L., Windhorst, S.
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(2018). Lymphocyte specific protein-1 regulates mechanosensory oscillation of podosomes and actin isoform-based actomyosin symmetry breaking. Nat. Commun. 9, 515
Cervero, P., Wiesner, C., Bouissou, A., Poincloux, R., Linder, S.
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(2018). Structural and Functional Analyses of the Shedding Protease ADAM17 in HoxB8-Immortalized Macrophages and Dendritic-like Cells J. Immunol. 201(10):3106-3118
Cabron, A.-S., El Azzouzi, K., Schwarz, J., Boss, M.,Arnold, P., Chalaris-Rissmann, A., Schumacher, N., Renné, T., Taylor, P.T., Linder, S., Rose-John, S., Zunke, F.
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(2019). Probing the mechanical landscape: new insights into podosome architecture and mechanics. J. Cell Sci. 132(24), 1-11
van den Dries, K. Linder S., Maridonneau-Parini, I., Poincloux, R.
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(2020). Nucleobindin-1 regulates extracellular matrix degradation by promoting intra-Golgi trafficking of matrix metalloproteinases. J. Cell Biol., 219(8)
Pacheco-Fernandez, N., Pakdel, M., Blank, B., Sanchez-Gonzalez, I., Gautsch, R., Weber, K., Hausser, A., Linder, S., von Blume, J.
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(2020). Poji: a Fiji-based tool for analysis of podosomes and associated proteins. J. Cell Sci. 133(8)
Herzog, R., van den Dries, K., Cervero, P., Linder, S.
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(2020). The podosome cap: past, present, perspective. Eur. J. Cell. Biol. 99(5)
Linder S., Cervero, P.
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(2021). Cargo-specific recruitment in clathrin and dynamin-independent endocytosis. Nat. Cell Biol.
Moreno-Layseca, P., Jäntti, N.Z., Godbole, R., Sommer, C., Jacquemet, G., Al-Akhrass, H., Kronqvist, P., Oliveira-Ferrer, L., Cervero, P., Linder, S., Aepfelbacher, M., Rae, J., Parton, R.G., Disanza, A., Scita, G., Mayor, S., Selbach, M., Veltel, S., Ivaska, J.
