A new transcriptional role for matrix metalloproteinase-12 in antiviral immunity.

TitleA new transcriptional role for matrix metalloproteinase-12 in antiviral immunity.
Publication TypeJournal Article
Year of Publication2014
AuthorsMarchant, DJ, Bellac, CL, Moraes, TJ, Wadsworth, SJ, Dufour, A, Butler, GS, Bilawchuk, LM, Hendry, RG, A Robertson, G, Cheung, CT, Ng, J, Ang, L, Luo, Z, Heilbron, K, Norris, MJ, Duan, W, Bucyk, T, Karpov, A, Devel, L, Georgiadis, D, Hegele, RG, Luo, H, Granville, DJ, Dive, V, McManus, BM, Overall, CM
JournalNat Med
Volume20
Issue5
Pagination493-502
Date Published2014 May
ISSN1546-170X
KeywordsAnimals, 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.

DOI10.1038/nm.3508
Alternate JournalNat. Med.
PubMed ID24784232
Grant List08-0369 / / Canadian Institutes of Health Research / Canada
MOP-111055 / / Canadian Institutes of Health Research / Canada
MOP-37937 / / Canadian Institutes of Health Research / Canada