TY - JOUR
TI - A new transcriptional role for matrix metalloproteinase-12 in antiviral immunity
AU - Marchant, D.J.
AU - Bellac, C.L.
AU - Moraes, T.J.
AU - Wadsworth, S.J.
AU - Dufour, A.
AU - Butler, G.S.
AU - Bilawchuk, L.M.
AU - Hendry, R.G.
AU - Robertson, A.G.
AU - Cheung, C.T.
AU - Ng, J.
AU - Ang, L.
AU - Luo, Z.
AU - Heilbron, K.
AU - Norris, M.J.
AU - Duan, W.
AU - Bucyk, T.
AU - Karpov, A.
AU - Devel, L.
AU - Georgiadis, D.
AU - Hegele, R.G.
AU - Luo, H.
AU - Granville, D.J.
AU - Dive, V.
AU - McManus, B.M.
AU - Overall, C.M.
JO - Journal of Natural Medicines
PY - 2014
VL - 20
TODO - 5
SP - 493-502
PB - Nature Publishing Group
SN - 1861-0293
TODO - 10.1038/nm.3508
TODO - 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
TODO - 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.
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