Journal
NATURE MEDICINE
Volume 20, Issue 5, Pages 497-506Publisher
NATURE RESEARCH
DOI: 10.1038/nm.3508
Keywords
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Funding
- Canadian Institutes of Health Research [08-0369, MOP-37937, MOP-111055]
- Michael Smith Research Foundation (University of British Columbia Centre for Blood Research)
- British Columbia Proteomics Network
- Canada Research Chair in Viral Pathogenesis
- US Myocarditis Foundation
- Heart and Stroke Foundation of Canada
- Heart and Stroke Foundation of British Columbia
- Heart and Stroke Foundation of Yukon
- Canada Research Chair in Metalloproteinase Proteomics and Systems Biology
- Genome Canada/British Columbia
- Networks of Centres of Excellence-CECR Centre of Excellence for Prevention of Organ Failure
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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.
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