ArticleNature medicine2014
A new transcriptional role for matrix metalloproteinase-12 in antiviral immunity.
Article in Nature medicine, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 124 papers.
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Who cites it
124 citing papers in PubMed, 261 citations in OpenAlex.
- TRPA1 Regulates Fibrosis-Associated Transcriptional Pathways in Human Lung Epithelial Cells.Basic & clinical pharmacology & toxicology · 2026Article
- Proximity-Induced Transfer of a Mass Tag Enables Direct Profiling of Active Matrix Metalloproteases.Angewandte Chemie (International ed. in English) · 2026Article
- EZH2 enhances PCV2 replication through inhibition of MMP1 and MMP12 transcription activity.Veterinary research · 2026Article
- MMP-3 cleavage of Lamin A induces pro-migratory nuclear deformity, nucleophagy, and their autophagic secretion with extracellular vesicles in metastatic cancer.Cell communication and signaling : CCS · 2026Article
- BACE1 regulates sleep-wake cycle through both enzymatic and non-enzymatic actions.EMBO reports · 2026Article
- Extracellular matrix in vascular homeostasis and disease.Nature reviews. Cardiology · 2025Review
- N-terminomics and proteomics analysis of Calpain-2 reveal key proteolytic processing of metabolic and cell adhesion proteins.Protein science : a publication of the Protein Society · 2025Article
- Article
- Review
- Covalent Labeling of Matrix Metalloproteases with Affinity-Based Probes Containing Tuned Reactive N-Acyl-N-Alkyl Sulfonamide Cleavable Linkers.Chembiochem : a European journal of chemical biology · 2024Article
- Human monocyte-derived macrophages shift subcellular metalloprotease activity depending on their activation state.iScience · 2024Article
- Limited Alleviation of Lysosomal Acid Lipase Deficiency by Deletion of Matrix Metalloproteinase 12.International journal of molecular sciences · 2024Article
- Implications of MMP-12 in the pathophysiology of ischaemic stroke.Stroke and vascular neurology · 2024Review
- Redefining metalloproteases specificity through network proteolysis.Trends in molecular medicine · 2024Review
- Matrix metalloproteinase-8 regulates dendritic cell tolerance in late polymicrobial sepsis via the nuclear factor kappa-B p65/β-catenin pathway.Burns & trauma · 2024Article
- Genetic deletion of MMP12 ameliorates cardiometabolic disease by improving insulin sensitivity, systemic inflammation, and atherosclerotic features in mice.Cardiovascular diabetology · 2023Article
- Paracrine regulation of neural crest EMT by placodal MMP28.PLoS biology · 2023Article
- Matrix Metalloproteinases Inhibitors in Cancer Treatment: An Updated Review (2013-2023).Molecules (Basel, Switzerland) · 2023Review
- Article
- Imbalance of Pulmonary Microvascular Endothelial Cell-Expression of Metalloproteinases and Their Endogenous Inhibitors Promotes Septic Barrier Dysfunction.International journal of molecular sciences · 2023Article
64 more citing papers are in PubMed but not listed here.
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Authors and funding
26 authors at 8 institutions in 2 countries.
Funding
Abstract
Interferon-α (IFN-α) is essential for antiviral immunity, but in the absence of matrix metalloproteinase-12 (MMP-12) or IκBα (encoded by NFKBIA) we show that IFN-α is retained in the cytosol of virus-infected cells and is not secreted. Our findings suggest that activated IκBα mediates the export of IFN-α from virus-infected cells and that the inability of cells in Mmp12(-/-) but not wild-type mice to express IκBα and thus export IFN-α makes coxsackievirus type B3 infection lethal and renders respiratory syncytial virus more pathogenic. We show here that after macrophage secretion, MMP-12 is transported into virus-infected cells. In HeLa cells MMP-12 is also translocated to the nucleus, where it binds to the NFKBIA promoter, driving transcription. We also identified dual-regulated substrates that are repressed both by MMP-12 binding to the substrate's gene exons and by MMP-12-mediated cleavage of the substrate protein itself. Whereas intracellular MMP-12 mediates NFKBIA transcription, leading to IFN-α secretion and host protection, extracellular MMP-12 cleaves off the IFN-α receptor 2 binding site of systemic IFN-α, preventing an unchecked immune response. Consistent with an unexpected role for MMP-12 in clearing systemic IFN-α, treatment of coxsackievirus type B3-infected wild-type mice with a membrane-impermeable MMP-12 inhibitor elevates systemic IFN-α levels and reduces viral replication in pancreas while sparing intracellular MMP-12. These findings suggest that inhibiting extracellular MMP-12 could be a new avenue for the development of antiviral treatments.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.