@article{3087617,
    title = "A new transcriptional role for matrix metalloproteinase-12 in antiviral immunity",
    author = "Marchant, D.J. and Bellac, C.L. and Moraes, T.J. and Wadsworth, S.J. and Dufour, A. and Butler, G.S. and Bilawchuk, L.M. and Hendry, R.G. and Robertson, A.G. and Cheung, C.T. and Ng, J. and Ang, L. and Luo, Z. and Heilbron, K. and Norris, M.J. and Duan, W. and Bucyk, T. and Karpov, A. and Devel, L. and Georgiadis, D. and Hegele, R.G. and Luo, H. and Granville, D.J. and Dive, V. and McManus, B.M. and Overall, C.M.",
    journal = "Journal of Natural Medicines",
    year = "2014",
    volume = "20",
    number = "5",
    pages = "493-502",
    publisher = "Nature Publishing Group",
    issn = "1861-0293",
    doi = "10.1038/nm.3508",
    keywords = "alpha interferon;  I kappa B kinase alpha;  macrophage elastase;  matrix metalloproteinase;  alpha interferon;  I kappa B;  macrophage elastase;  NF kappaB inhibitor alpha;  NF-kappaB inhibitor alpha, Article;  cell nucleus;  controlled study;  coxsackievirus type B3 infection;  Enterovirus infection;  HeLa cell line;  human;  human cell;  Human respiratory syncytial virus;  immune response;  nonhuman;  priority journal;  virus immunity;  animal;  article;  binding site;  cell nucleus;  cytosol;  drug effect;  genetics;  immunity;  immunology;  knockout mouse;  metabolism;  mouse;  pancreas;  pathogenicity;  Rous sarcoma oncovirus;  virology;  virus replication, Animals;  Binding Sites;  Cell Nucleus;  Cytosol;  HeLa Cells;  Humans;  I-kappa B Proteins;  Immunity;  Interferon-alpha;  Matrix Metalloproteinase 12;  Mice;  Mice, Knockout;  Pancreas;  Rous sarcoma virus;  Virus Replication",
    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. © 2014, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved."
}