A new transcriptional role for matrix metalloproteinase-12 in antiviral immunity.
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.
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.
David J
DJ
Marchant
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.
Caroline L
CL
Bellac
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Theo J
TJ
Moraes
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.
Samuel J
SJ
Wadsworth
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.
Antoine
A
Dufour
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.
Georgina S
GS
Butler
Li Ka Shing Institute of Virology, Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada.
Leanne M
LM
Bilawchuk
Li Ka Shing Institute of Virology, Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada.
Reid G
RG
Hendry
Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
A Gordon
AG
Robertson
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.
Caroline T
CT
Cheung
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.
Julie
J
Ng
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.
Lisa
L
Ang
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.
Zongshu
Z
Luo
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.
Karl
K
Heilbron
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Michael J
MJ
Norris
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Wenming
W
Duan
Li Ka Shing Institute of Virology, Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada.
Taylor
T
Bucyk
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.
Andrei
A
Karpov
Commissariat a l'Energie Atomique, Labex LERMIT, Service d'Ingenierie Moleculaire des Proteines, Gif/Yvette, France.
Laurent
L
Devel
1] Commissariat a l'Energie Atomique, Labex LERMIT, Service d'Ingenierie Moleculaire des Proteines, Gif/Yvette, France. [2].
Dimitris
D
Georgiadis
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Richard G
RG
Hegele
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.
Honglin
H
Luo
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.
David J
DJ
Granville
Commissariat a l'Energie Atomique, Labex LERMIT, Service d'Ingenierie Moleculaire des Proteines, Gif/Yvette, France.
Vincent
V
Dive
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].
Bruce M
BM
McManus
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].
Christopher M
CM
Overall
D000818:Animals; D001665:Binding Sites; D002467:Cell Nucleus / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism / Q000821:virology; D006367:HeLa Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D007109:Immunity / Q000235:genetics*; D016898:Interferon-alpha / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D053508:Matrix Metalloproteinase 12 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D000072000:NF-KappaB Inhibitor alpha; D010179:Pancreas / Q000276:immunology / Q000821:virology; D052736:Rous sarcoma virus / Q000235:genetics / Q000472:pathogenicity; D014779:Virus Replication / Q000187:drug effects
D020672:I-kappa B Proteins; D016898:Interferon-alpha; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D000072000:NF-KappaB Inhibitor alpha; D053508:Matrix Metalloproteinase 12