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S100A4 regulates macrophage invasion by distinct myosin-dependent and myosin-independent mechanisms
Natalya G Dulyaninova1, Penelope D Ruiz2, Matthew J Gamble2
1Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461.
Abstract:
S100A4, a member of the S100 family of Ca2+-binding proteins, is a key regulator of cell migration and invasion. Our previous studies showed that bone marrow-derived macrophages from S100A4-/- mice exhibit defects in directional motility and chemotaxis in vitro and reduced recruitment to sites of inflammation in vivo. We now show that the loss of S100A4 produces two mechanistically distinct phenotypes with regard to macrophage invasion: a defect in matrix degradation, due to a disruption of podosome rosettes caused by myosin-IIA overassembly, and a myosin-independent increase in microtubule acetylation, which increases podosome rosette stability and is sufficient to inhibit macrophage invasion. Our studies point to S100A4 as a critical regulator of matrix degradation, whose actions converge on the dynamics and degradative functions of podosome rosettes.
Insights
The S100A4 protein is crucial for macrophage invasion and matrix degradation. Its absence disrupts podosome rosettes, impairing cell movement and leading to distinct invasion defects.
Area of Science:
- Cell Biology
- Molecular Biology
- Immunology
Background:
- S100A4 is a calcium-binding protein regulating cell migration and invasion.
- S100A4 deficiency in mice impairs macrophage motility and inflammatory recruitment.
- Macrophage invasion is essential for inflammatory responses and tissue repair.
Purpose of the Study:
- To elucidate the specific mechanisms by which S100A4 influences macrophage invasion.
- To investigate the role of S100A4 in regulating matrix degradation and podosome dynamics.
- To identify novel pathways affected by S100A4 loss in macrophages.
Main Methods:
- Analysis of macrophage invasion and matrix degradation in S100A4 knockout mice.
- Investigation of podosome rosette structure and function.
- Assessment of myosin-IIA assembly and microtubule acetylation levels.
Main Results:
- Loss of S100A4 leads to impaired matrix degradation via disrupted podosome rosettes due to myosin-IIA overassembly.
- S100A4 deficiency causes myosin-independent microtubule hyperacetylation, stabilizing podosome rosettes.
- These combined defects significantly inhibit macrophage invasion.
Conclusions:
- S100A4 is a critical regulator of macrophage matrix degradation and invasion.
- S100A4's function converges on the dynamics and degradative capacity of podosome rosettes.
- Targeting S100A4 pathways may offer therapeutic strategies for inflammatory diseases.
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