| Autor: |
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. |
| Jazyk: |
angličtina |
| Rok vydání: |
2014 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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