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

  • Nat Med. 2014 May;20(5):493-502. doi: 10.1038/nm.3508.
David J Marchant  1 ,  Caroline L Bellac  2 ,  Theo J Moraes  3 ,  Samuel J Wadsworth  4 ,  Antoine Dufour  2 ,  Georgina S Butler  2 ,  Leanne M Bilawchuk  5 ,  Reid G Hendry  5 ,  A Gordon Robertson  6 ,  Caroline T Cheung  4 ,  Julie Ng  4 ,  Lisa Ang  4 ,  Zongshu Luo  4 ,  Karl Heilbron  4 ,  Michael J Norris  3 ,  Wenming Duan  3 ,  Taylor Bucyk  5 ,  Andrei Karpov  4 ,  Laurent Devel  7 ,  Dimitris Georgiadis  8 ,  Richard G Hegele  3 ,  Honglin Luo  4 ,  David J Granville  4 ,  Vincent Dive  7 ,  Bruce M McManus  9 ,  Christopher M Overall  10
Affiliations
  • 1. 1] Department of Pathology and Laboratory Medicine, UBC James Hogg Research Centre, Institute for Heart + Lung Health, St. Paul's Hospital/Providence Health Care/University of British Columbia, Vancouver, British Columbia, Canada. [2] Li Ka Shing Institute of Virology, Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada.
  • 2. 1] Department of Oral Biological & Medical Sciences, University of British Columbia, Vancouver, British Columbia, Canada. [2] Department of Biochemistry & Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada. [3] Centre for Blood Research, Life Sciences Institute, Faculty of Dentistry, University of British Columbia, Vancouver, British Columbia, Canada.
  • 3. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
  • 4. Department of Pathology and Laboratory Medicine, UBC James Hogg Research Centre, Institute for Heart + Lung Health, St. Paul's Hospital/Providence Health Care/University of British Columbia, Vancouver, British Columbia, Canada.
  • 5. Li Ka Shing Institute of Virology, Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada.
  • 6. Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
  • 7. Commissariat a l'Energie Atomique, Labex LERMIT, Service d'Ingenierie Moleculaire des Proteines, Gif/Yvette, France.
  • 8. 1] Commissariat a l'Energie Atomique, Labex LERMIT, Service d'Ingenierie Moleculaire des Proteines, Gif/Yvette, France. [2].
  • 9. 1] Department of Pathology and Laboratory Medicine, UBC James Hogg Research Centre, Institute for Heart + Lung Health, St. Paul's Hospital/Providence Health Care/University of British Columbia, Vancouver, British Columbia, Canada. [2].
  • 10. 1] Department of Oral Biological & Medical Sciences, University of British Columbia, Vancouver, British Columbia, Canada. [2] Department of Biochemistry & Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada. [3] Centre for Blood Research, Life Sciences Institute, Faculty of Dentistry, University of British Columbia, Vancouver, British Columbia, Canada. [4].
PMID: 24784232 DOI: 10.1038/nm.3508
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.