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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

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

Abstract

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.

PMID:
26159719
PMCID:
PMC4505794
DOI:
10.1016/j.chom.2015.06.007
[Indexed for MEDLINE]
Free PMC Article

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