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

• Published in: Nature medicine Vol. 20; no. 5; pp. 493 - 502
• Main Authors: Marchant, David J, Bellac, Caroline L, Moraes, Theo J, Wadsworth, Samuel J, Dufour, Antoine, Butler, Georgina S, Bilawchuk, Leanne M, Hendry, Reid G, Robertson, A Gordon, Cheung, Caroline T, Ng, Julie, Ang, Lisa, Luo, Zongshu, Heilbron, Karl, Norris, Michael J, Duan, Wenming, Bucyk, Taylor, Karpov, Andrei, Devel, Laurent, Georgiadis, Dimitris, Hegele, Richard G, Luo, Honglin, Granville, David J, Dive, Vincent, McManus, Bruce M, Overall, Christopher M
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.05.2014; Nature Publishing Group
• Subjects: 14; 14/19; 49; 49/15; 631/250/255/2514; 64; 64/60; 82; 82/51; 82/58; 96; Analysis; Animals; Antiviral drugs; Binding Sites; Biomedicine; Cancer Research; Cell Nucleus - genetics; Cell Nucleus - immunology; Cell Nucleus - metabolism; Coxsackievirus; Cytosol - metabolism; Cytosol - virology; Enzymes; HeLa Cells; Humans; I-kappa B Proteins - genetics; I-kappa B Proteins - metabolism; Immune response; Immunity; Immunity - genetics; Immunology; Infectious Diseases; Interferon; Interferon-alpha - genetics; Interferon-alpha - immunology; Interferon-alpha - metabolism; Matrix Metalloproteinase 12 - genetics; Matrix Metalloproteinase 12 - metabolism; Metabolic Diseases; Mice; Mice, Knockout; Molecular Medicine; Neurosciences; NF-KappaB Inhibitor alpha; Pancreas - immunology; Pancreas - virology; Physiological aspects; Proteases; Respiratory syncytial virus; Rous sarcoma virus - genetics; Rous sarcoma virus - pathogenicity; Substrates; Transcription factors; Virus Replication - drug effects
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.3508

Matrix metalloproteinases (MMPs) normally act extracellularly. Now Marchant et al . report an unexpected nuclear activity for MMP-12 in virus-infected cells in regulating transcription of the gene encoding IκBα and affecting secretion of interferon-α. 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.