DNA-PK Is Targeted by Multiple Vaccinia Virus Proteins to Inhibit DNA Sensing.
Scutts, Simon R
Ember, Stuart W
Veyer, David L
Sumner, Rebecca P
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Scutts, S. R., Ember, S. W., Ren, H., Ye, C., Lovejoy, C. A., Mazzon, M., Veyer, D. L., et al. (2018). DNA-PK Is Targeted by Multiple Vaccinia Virus Proteins to Inhibit DNA Sensing.. Cell reports, 25 (7), 1953-1965.e4. https://doi.org/10.1016/j.celrep.2018.10.034
Virus infection is sensed by pattern recognition receptors (PRRs) detecting virus nucleic acid and initiating an innate immune response. DNA-dependent protein kinase (DNA-PK) is a PRR that binds cytosolic DNA and is antagonised by vaccinia virus (VACV) protein C16. Here, VACV protein C4 is also shown to antagonise DNA-PK by binding to Ku and blocking Ku binding to DNA, leading to reduced production of cytokines and chemokines in vivo and diminished recruitment of inflammatory cells. C4 and C16 share redundancy in that a double deletion virus has reduced virulence not seen with single deletion viruses following intradermal infection. However, non-redundant functions exist because both single deletion viruses display attenuated virulence compared to wild-type VACV after intranasal infection. It is notable that VACV expresses two proteins to antagonise DNA-PK, but is not known to target other DNA sensors, emphasising the importance of this PRR in the response to infection in vivo.
T-Lymphocytes, Hela Cells, Animals, Mice, Inbred BALB C, Mice, Inbred C57BL, Humans, Vaccinia virus, Viral Proteins, DNA, Cytokines, Administration, Intranasal, Mutagenesis, Site-Directed, Lymphocyte Activation, Virulence, Protein Binding, Female, DNA-Activated Protein Kinase, Immunity, Innate, Protein Multimerization, HEK293 Cells, Ku Autoantigen
Wellcome Trust (090315) Lister Institute
Wellcome Trust (090315/B/09/Z)
WELLCOME TRUST (090315/B/09/A)
External DOI: https://doi.org/10.1016/j.celrep.2018.10.034
This record's URL: https://www.repository.cam.ac.uk/handle/1810/286397
Attribution-NonCommercial-NoDerivatives 4.0 International
Licence URL: https://creativecommons.org/licenses/by-nc-nd/4.0/