Tools of the trade: podosomes as multipurpose organelles of monocytic cells

Abstract

Podosomes are adhesion and invasion structures that are particularly prominent in cells of the monocytic lineage such as macrophages, dendritic cells, and osteoclasts. They are multifunctional organelles that combine several key abilities required for cell migration and invasion. The podosome repertoire includes well-established functions such as cell-substrate adhesion, and extracellular matrix degradation, recently discovered abilities such as rigidity and topology sensing as well as antigen sampling, and also more speculative functions such as cell protrusion stabilization and transmigration. Collectively, podosomes not only enable dynamic interactions of cells with their surroundings, they also gather information about the pericellular environment, and are actively involved in its reshaping. This review presents an overview of the current knowledge on podosome composition, architecture, and regulation. We focus in particular on the growing list of podosome functions and discuss the specific properties of podosomes in macrophages, dendritic cells, and osteoclasts. Moreover, this article highlights podosome-related intracellular transport processes, the formation of podosomes in 3D environments as well as potentially podosome-associated diseases involving monocytic cells.

The formins FHOD1 and INF2 regulate inter- and intra-structural contractility of podosomes

“…Moreover, the protrusive force of podosomes, which is in the 10 2 -10 3 nN range, shows a similar periodicity, with cycles of 40-50 s (Labernadie et al, 2014). The current model thus pictures podosomes as a contractile system, constantly balancing forces generated by actin polymerization in the core and by the lateral actin cables that function as springs (Labernadie et al, 2014), ultimately enabling podosomes to function as mechanosensory devices (Linder and Wiesner, 2015). We now show that siRNA-mediated knockdown of INF2 leads to a ∼25% dampening of podosome oscillations, pointing to a role of INF2 in the mechanosensing ability of these structures.…”

“…In order to fulfill their functions during immune surveillance, they have to cross tissue barriers and navigate through the dense meshwork of the extracellular matrix (ECM) (Hynes, 2009), which often involves proteolytic cleavage of ECM material (Sabeh et al, 2009). Accordingly, macrophages are able to form actin-rich podosomes at the cell-substrate interface that function as both sites of adhesion and hotspots of matrix degradation (Linder and Aepfelbacher, 2003;Linder and Wiesner, 2015;Murphy and Courtneidge, 2011). Podosomes are able to locally degrade the matrix through recruitment of matrix-lytic enzymes, in particular of the matrix metalloproteinase family (Linder, 2007).…”

Tensin 3 is a new partner of Dock5 that controls osteoclast podosome organization and activity

“…Phosphorylation of β-integrin tail by Src has been shown to displace talin and allow the binding of tensin (McCleverty et al, 2007). Taking these observations together, one could speculate that during podosome patterning, which is Src dependent (Destaing et al, 2008), tensin 3 molecules could functions as a bridge to connect the β3 integrin layer and Dock5 within the above acto-myosin layer, which runs between podosomes (Linder and Wiesner, 2015). This would allow podosomes to get closer to one another upon their patterning into rings and the belt (Luxenburg et al, 2007).…”

“…The latter contains two actomyosin networks: one that connects podosomes to the substrate through αvβ3 integrin, and one that interconnects podosomes (Linder and Wiesner, 2015). Several proteins were identified at the podosome cloud that contribute to the ability of osteoclasts to rearrange podosomes into the belt structure and build the bone-resorbing apparatus, including Dock5 (Vives et al, 2011), Vav3 (Faccio et al, 2005), vinculin (Fukunaga et al, 2014), FARP2 (Takegahara et al, 2010) and Pyk2 (Gil-Henn et al, 2007).…”

Adhesion kinetics of human primary monocytes, dendritic cells, and macrophages: Dynamic cell adhesion measurements with a label-free optical biosensor and their comparison with end-point assays

“…For instance, podosomes-the multifunctional adhesive and invasive structures that are particularly prominent in the monocytic lineage-are deeply engaged in both cell-substrate adhesion and matrix degradation. 51 Thus, we can speculate that within the first hour after cell seeding the biosensor signal was dominated by the spreading process, but then another effect turned on. This could be related to the transition of the cell shape from rounded to more complex shapes with long protrusions suggested by the imaging of cells during spreading (data not shown).…”