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

Nat Med. 2014 May;20(5):493-502. doi: 10.1038/nm.3508. Epub 2014 Apr 28.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Cell Nucleus / genetics*
  • Cell Nucleus / immunology
  • Cell Nucleus / metabolism
  • Cytosol / metabolism
  • Cytosol / virology
  • HeLa Cells
  • Humans
  • I-kappa B Proteins / genetics
  • I-kappa B Proteins / metabolism
  • Immunity / genetics*
  • Interferon-alpha / genetics*
  • Interferon-alpha / immunology
  • Interferon-alpha / metabolism
  • Matrix Metalloproteinase 12 / genetics*
  • Matrix Metalloproteinase 12 / metabolism
  • Mice
  • Mice, Knockout
  • NF-KappaB Inhibitor alpha
  • Pancreas / immunology
  • Pancreas / virology
  • Rous sarcoma virus / genetics
  • Rous sarcoma virus / pathogenicity
  • Virus Replication / drug effects

Substances

  • I-kappa B Proteins
  • Interferon-alpha
  • NFKBIA protein, human
  • Nfkbia protein, mouse
  • NF-KappaB Inhibitor alpha
  • Matrix Metalloproteinase 12