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Metalloproteinase MT1-MMP islets act as memory devices for podosome reemergence
Karim El Azzouzi1, Christiane Wiesner1, Stefan Linder2
1Institut für medizinische Mikrobiologie, Virologie und Hygiene, Universitätsklinikum Eppendorf, 20246 Hamburg, Germany.
Abstract:
Podosomes are dynamic cell adhesions that are also sites of extracellular matrix degradation, through recruitment of matrix-lytic enzymes, particularly of matrix metalloproteinases. Using total internal reflection fluorescence microscopy, we show that the membrane-bound metalloproteinase MT1-MMP is enriched not only at podosomes but also at distinct "islets" embedded in the plasma membrane of primary human macrophages. MT1-MMP islets become apparent upon podosome dissolution and persist beyond podosome lifetime. Importantly, the majority of MT1-MMP islets are reused as sites of podosome reemergence. siRNA-mediated knockdown and recomplementation analyses show that islet formation is based on the cytoplasmic tail of MT1-MMP and its ability to bind the subcortical actin cytoskeleton. Collectively, our data reveal a previously unrecognized phase in the podosome life cycle and identify a structural function of MT1-MMP that is independent of its proteolytic activity. MT1-MMP islets thus act as cellular memory devices that enable efficient and localized reformation of podosomes, ensuring coordinated matrix degradation and invasion.
Insights
New research reveals that membrane-type 1 matrix metalloproteinase (MT1-MMP) forms "islets" in macrophage membranes. These islets act as memory devices, facilitating efficient podosome reformation and matrix degradation.
Area of Science:
- Cell Biology
- Biochemistry
- Molecular Biology
Background:
- Podosomes are dynamic cell adhesions crucial for extracellular matrix (ECM) degradation.
- Matrix metalloproteinases (MMPs), particularly MT1-MMP, are key enzymes involved in ECM remodeling.
- The precise spatiotemporal regulation of MT1-MMP at podosomes is not fully understood.
Purpose of the Study:
- To investigate the localization and function of MT1-MMP during the podosome life cycle in primary human macrophages.
- To identify novel roles of MT1-MMP beyond its proteolytic activity.
- To elucidate the mechanisms governing MT1-MMP dynamics at the cell surface.
Main Methods:
- Total internal reflection fluorescence microscopy (TIRFM) was employed to visualize MT1-MMP dynamics in live cells.
- RNA interference (siRNA) was used to knock down MT1-MMP expression.
- Recomplementation experiments were performed to assess the role of MT1-MMP domains.
Main Results:
- MT1-MMP localizes not only to podosomes but also to distinct plasma membrane "islets" that appear after podosome dissolution.
- These MT1-MMP islets persist and serve as sites for subsequent podosome reassembly.
- Islet formation depends on the cytoplasmic tail of MT1-MMP and its interaction with the subcortical actin cytoskeleton.
Conclusions:
- MT1-MMP islets represent a previously unrecognized phase in the podosome life cycle.
- MT1-MMP possesses a structural function, independent of its enzymatic activity, in regulating podosome formation.
- MT1-MMP islets function as cellular memory, ensuring efficient and localized podosome reformation for coordinated matrix degradation and invasion.
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