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Cell Host Microbe. 2015 Jul 8;18(1):61-74. doi: 10.1016/j.chom.2015.06.007.

Flavivirus Antagonism of Type I Interferon Signaling Reveals Prolidase as a Regulator of IFNAR1 Surface Expression.

Author information

  • 1Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, MT 59840, USA.
  • 2Department of Microbiology, University of Washington, Seattle, WA 98109, USA.
  • 3Department of Medical Microbiology and Immunology, College of Medicine, University of Toledo Health Science Campus, Toledo, OH 43614, USA.
  • 4Translational Medicine Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA.
  • 5Laboratory of Public Health, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, 060-0818, Japan.
  • 6Metabolic, Cardiovascular and Inflammatory Disease Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
  • 7Immunopathogenesis Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20814, USA.
  • 8Department of Molecular Medicine, Biochemistry Unit, University of Pavia, 27100 Pavia, Italy.
  • 9Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, MT 59840, USA. Electronic address:


Type I interferon (IFN-α/β or IFN-I) signals through two receptor subunits, IFNAR1 and IFNAR2, to orchestrate sterile and infectious immunity. Cellular pathways that regulate IFNAR1 are often targeted by viruses to suppress the antiviral effects of IFN-I. Here we report that encephalitic flaviviruses, including tick-borne encephalitis virus and West Nile virus, antagonize IFN-I signaling by inhibiting IFNAR1 surface expression. Loss of IFNAR1 was associated with binding of the viral IFN-I antagonist, NS5, to prolidase (PEPD), a cellular dipeptidase implicated in primary immune deficiencies in humans. Prolidase was required for IFNAR1 maturation and accumulation, activation of IFNβ-stimulated gene induction, and IFN-I-dependent viral control. Human fibroblasts derived from patients with genetic prolidase deficiency exhibited decreased IFNAR1 surface expression and reduced IFNβ-stimulated signaling. Thus, by understanding flavivirus IFN-I antagonism, prolidase is revealed as a central regulator of IFN-I responses.

Copyright © 2015 Elsevier Inc. All rights reserved.

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[Available on 2016-07-08]
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