Cell Biology More Than a Protease

Annalisa M. VanHook

Science Signaling, AAAS, Washington, DC 20005, USA

Matrix metalloproteases (MMPs) are often associated with extracellular matrix (ECM) remodeling and tissue invasion by cells such as macrophages and cancer cells. Shimizu-Hirota et al. report that MT1-MMP, a membrane-anchored MMP that enables invasion of collagen-rich tissues by various cell types, is required in macrophages as a regulator of gene expression. Despite showing reduced protease activity in vitro, macrophages from MT1-MMP^–/– mice had normal migratory, chemotactic, and invasive activities in both 2D and 3D culture and invaded tissues normally in vivo, indicating that MT1-MMP was not solely responsible for ECM remodeling by macrophages. After treatment with bacterial lipopolysaccharide in vitro or in mice, MT1-MMP^–/– macrophages showed a proinflammatory phenotype characterized by increased expression of proinflammatory genes that are normally repressed by the chromatin remodeling complex Mi-2/NuRD and decreased expression of IL-10 (which encodes an anti-inflammatory cytokine) relative to wild-type (WT) macrophages. Expression of transcripts encoding components of the Mi-2/NuRD complex was reduced in MT1-MMP^–/– macrophages, and Mi-2 was detected at the promoter of the gene encoding the proinflammatory cytokine IL-12b. Phosphoinositide 3-kinase (PI3K)–Akt signaling is also an important modulator of inflammatory responses, and expression of p110, which encodes the catalytic subunit of PI3K, was reduced in MT1-MMP^–/– macrophages. Pharmacological inhibition of PI3K signaling in WT macrophages phenocopied the MT1-MMP^–/– proinflammatory phenotype. The protease activity of MT1-MMP was dispensable for gene regulation because an MMP inhibitor had no effect on p110 expression in WT macrophages, and expression of catalytically inactive forms of MT1-MMP rescued the proinflammatory phenotype of MT1-MMP^–/– macrophages. Full-length and various mutant forms of MT1-MMP rescued transcriptional responses in MT1-MMP^–/– macrophages, and each form translocated to the nucleus in both WT and MT1-MMP^–/– macrophages. In contrast, a secreted form of MT1-MMP did not rescue the transcriptional response or translocate to nuclei. MT1-MMP was detected at the p110 promoter and stimulated expression of a p110 reporter, suggesting that it acted as a transcriptional coactivator. Thus, in addition to participating in ECM remodeling, MT1-MMP stimulates expression of a PI3K signaling component to modulate expression of immune response genes under control of the Mi-2/NuRD complex.

R. Shimizu-Hirota, W. Xiong, B. T. Baxter, S. L. Kunkel, I. Maillard, X.-W. Chen, F. Sabeh, R. Liu, X.-Y. Li, S. J. Weiss, MT1-MMP regulates the PI3K·Mi-2/NuRD-dependent control of macrophage immune function. Genes Dev. 26, 395–413 (2012). [Abstract] [Full Text]

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Protease-Independent Invasion

Annalisa M. VanHook (8 January 2013)
Sci. Signal. 6 (257), ec5. [DOI: 10.1126/scisignal.2003942]
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