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

Interferon-alpha (IFN-alpha) is essential for antiviral immunity, but in the absence of matrix metalloproteinase-12 (MMP-12) or I kappa B alpha (encoded by NFKBIA) we show that IFN-alpha is retained in the cytosol of virus-infected cells and is not secreted. Our findings suggest that activated I kappa B alpha mediates the export of IFN-alpha from virus-infected cells and that the inability of cells in Mmp12(-/-) but not wild-type mice to express I kappa B alpha and thus export IFN-alpha 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 He La 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-alpha secretion and host protection, extracellular MMP-12 cleaves off the IFN-alpha receptor 2 binding site of systemic IFN-alpha, preventing an unchecked immune response. Consistent with an unexpected role for MMP-12 in clearing systemic IFN-alpha, treatment of coxsackievirus type B3-infected wild-type mice with a membrane-impermeable MMP-12 inhibitor elevates systemic IFN-alpha 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.