Περίληψη:
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.
Συγγραφείς:
Marchant, D.J.
Bellac, C.L.
Moraes, T.J.
Wadsworth, S.J.
Dufour, A.
Butler, G.S.
Bilawchuk, L.M.
Hendry, R.G.
Robertson, A.G.
Cheung, C.T.
Ng, J.
Ang, L.
Luo, Z.
Heilbron, K.
Norris, M.J.
Duan, W.
Bucyk, T.
Karpov, A.
Devel, L.
Georgiadis, D.
Hegele, R.G.
Luo, H.
Granville, D.J.
Dive, V.
McManus, B.M.
Overall, C.M.
Λέξεις-κλειδιά:
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
