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.

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