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May the force be with the podosome

Macrophages, key cells of our immune system, probe their environment with adhesion structures called podosomes. Isabelle Maridonneau-Parini’s team at Institut de Pharmacologie et de Biologie Structurale has just determined the nanoscale architecture and the mechanics of these structures. Combining nanoscale 3D microscopy with protrusion force measurements made it possible to show that the podosome is an autonomous force generator that couples protrusion force and traction force. This work was published on March 29th, 2017 in ACS Nano.

 

Macrophages are immune cells that migrate through all tissues to defend our organism against pathogens and repair tissue damage. To migrate through the less porous tissues, these cells can form specific adhesion structures called podosomes, which enable them to probe the stiffness of, and degrade, the extracellular environment.

Recent work of Isabelle Maridonneau-Parini’s team showed that podosomes can exert a protrusive force on the extracellular matrix. According to the researchers’ hypothesis, protrusion forces must be counterbalanced by traction forces so that the podosome deforms the environment locally. In collaboration with researchers from Institut des Sciences Moléculaires, Orsay, Institut Langevin, Paris and Laboratoire d’Analyse et d’Architecture des Systèmes, Toulouse, the team has just provided an experimental proof that such a force balance exists.

Podosomes are submicrometer structures that consist of two modules: a protrusive core composed of actin filaments and a peripheral ring that adheres to the extracellular matrix. In order to study the mechanics of the adhesion ring, the expression of several ring components was inhibited and the impact on podosome protrusive ability was measured using atomic force microscopy. This approach showed that adhesion ring integrity is crucial for protrusive force generation at the core of the podosome. The adhesion ring would thus operate as a handle that transmits to the environment the force produced by the protrusive core. Using a tridimensional nanoscopy technique called DONALD (Direct Optical Nanoscopy with Axially Localized Detection), the researchers revealed that talin, one of the ring components, is vertically stretched within a molecular scaffold that connects adhesion receptors to the cytoskeleton and contains vinculin and paxillin. Talin stretching increases as the podosome generates higher protrusive forces, which proves that the ring is subjected to mechanical tension.

article-poincloux2.jpgFigure : Organization of proteins of the podosome adhesion ring and force generation. The podosome actin core is surrounded by a ring of proteins involved in adhesion to the extracellular matrix. This model shows the locations of, respectively, paxillin (purple), vinculin (light blue), talin (orange) and actin (green). Talin is shown in its extended conformation, which reveals traction force. Protrusion force generated by actin polymerization at the core is shown as the central arrow. This force is counterbalanced by traction force exerted at the ring (lateral arrows). Together, talin, vinculin and paxillin integrate tension and are involved in protrusive force generation. ©  Renaud Poincloux & Anaïs Bouissou

 

This fundamental result offers a new perspective on the workings of this structure developed by macrophages to migrate through dense environments.

article-poincloux1.jpgFigure : Podosomes are submicrometer structures that probe the stiffness of the extracellular environment. Topography of a flexible membrane deformed by the podosomes of a macrophage (atomic force microscopy). © Anaïs Bouissou.

article-poincloux3.jpgFigure : Architecture of the podosome ring (DONALD tridimensional nanoscopy); each vinculin molecule is colored according to its height with respect to the cell bottom (red to blue upwards). © Amsha Proag & Nicolas Bourg

 

 

Reference

Podosome Force Generation Machinery: A Local Balance between Protrusion at the Core and Traction at the Ring 
Anaïs Bouissou, Amsha Proag, Nicolas Bourg, Karine Pingris, Clément Cabriel,Stéphanie Balor, Thomas Mangeat, Christophe Thibault, Christophe Vieu,Guillaume Dupuis, Emmanuel Fort, Sandrine Lévêque-Fort, Isabelle Maridonneau-Parini, and Renaud Poincloux. ACS Nano. March 29, 2017. DOI: 10.1021/acsnano.7b00622

 

Contacts

Isabelle Maridonneau-Parini

Institut de Pharmacologie et de Biologie Structurale
CNRS UMR 5089, Université de Toulouse 
205 route de Narbonne
BP 64182 
31077 Toulouse Cedex 4

05 61 17 54 58

 

Renaud Poincloux

Institut de Pharmacologie et de Biologie Structurale
CNRS UMR 5089, Université de Toulouse 
205 route de Narbonne 
BP 64182 
31077 Toulouse Cedex 4

05 61 17 58 49


More informations (in french) HERE