Moonlighting roles for matrix metalloproteinases in transcription and interferon degradation during antiviral immunity Supervisor: Dr. David Marchant Department: Medical Microbiology and Immunology Institute: Li Ka Shing Institute of Virology Introduction - My laboratory investigates the innate antiviral roles of matrix metalloproteinases (MMPs) during cardio-pulmonary virus infection. MMPs are classically considered extracellular enzymes that cleave and degrade components of the extracellular matrix, playing key roles in wound repair and immune cell invasion into tissue. Our laboratory investigates novel roles for MMP12 during antiviral immunity. Intracellular MMP12 regulates antiviral alpha-interferon activity by moonlighting as a transcription factor in the nucleus to drive expression of mediators required for alpha-interferon secretion. Shortly after alpha-interferon is secreted, it is degraded by MMP12 because unregulated alpha-interferon is toxic. Therefore, the intracellular and extracellular roles of MMP12 work in tandem to regulate alpha-interferon, protecting the host from virus infection and alphainterferon toxicity, respectively. Finally, we are pursuing clinical utility of our findings by inhibiting MMP12 with a drug to increase one’s own natural alphainterferon levels during virus infection. Student Projects - Intracellular and transcriptional roles for MMPs are unprecedented and thus there is much work to be done to characterize this phenomenon. The DNA binding sequences for MMP12 are unknown so I am looking for a motivated student that is interested in determining the nucleotide binding sequences of MMP12. This project will involve protease inhibition assay, electrophoretic mobility shift assay and basic sub-cloning methods, to be learned and mastered. Additional projects include characterization of other MMPs that have recently been identified as transcription factors and examination of the cell biology of MMP action. If you would like to discuss the nature of this project and the studies available please feel free to contact me by email:
[email protected] Virus infection Antiviral immunity MMP-12 Degradation IFN-α MMP-12
Secreted
-12 MP α M IFN2 IFN-α MMP-1
MMP-12
