title: Flavivirus Antagonism of Type I Interferon Signaling Reveals Prolidase as a Regulator of IFNAR1 Surface Expression.
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.
authors.affiliation: Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, MT 59840, USA.
authors.forename: Kirk J
authors.initials: KJ
authors.lastname: Lubick
authors.affiliation: Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, MT 59840, USA.
authors.forename: Shelly J
authors.initials: SJ
authors.lastname: Robertson
authors.affiliation: Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, MT 59840, USA.
authors.forename: Kristin L
authors.initials: KL
authors.lastname: McNally
authors.affiliation: Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, MT 59840, USA.
authors.forename: Brett A
authors.initials: BA
authors.lastname: Freedman
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA 98109, USA.
authors.forename: Angela L
authors.initials: AL
authors.lastname: Rasmussen
authors.affiliation: Department of Medical Microbiology and Immunology, College of Medicine, University of Toledo Health Science Campus, Toledo, OH 43614, USA.
authors.forename: R Travis
authors.initials: RT
authors.lastname: Taylor
authors.affiliation: Translational Medicine Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Avram D
authors.initials: AD
authors.lastname: Walts
authors.affiliation: Laboratory of Public Health, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, 060-0818, Japan.
authors.forename: Seitaro
authors.initials: S
authors.lastname: Tsuruda
authors.affiliation: Laboratory of Public Health, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, 060-0818, Japan.
authors.forename: Mizuki
authors.initials: M
authors.lastname: Sakai
authors.affiliation: Laboratory of Public Health, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, 060-0818, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Ishizuka
authors.affiliation: Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, MT 59840, USA.
authors.forename: Elena F
authors.initials: EF
authors.lastname: Boer
authors.affiliation: Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, MT 59840, USA.
authors.forename: Erin C
authors.initials: EC
authors.lastname: Foster
authors.affiliation: Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, MT 59840, USA.
authors.forename: Abhilash I
authors.initials: AI
authors.lastname: Chiramel
authors.affiliation: Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, MT 59840, USA.
authors.forename: Conrad B
authors.initials: CB
authors.lastname: Addison
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA 98109, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Green
authors.affiliation: Metabolic, Cardiovascular and Inflammatory Disease Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Kastner
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA 98109, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Katze
authors.affiliation: Immunopathogenesis Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20814, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
authors.affiliation: Department of Molecular Medicine, Biochemistry Unit, University of Pavia, 27100 Pavia, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Forlino
authors.affiliation: Immunopathogenesis Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20814, USA.
authors.forename: Alexandra F
authors.initials: AF
authors.lastname: Freeman
authors.affiliation: Translational Medicine Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Manfred
authors.initials: M
authors.lastname: Boehm
authors.affiliation: Laboratory of Public Health, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, 060-0818, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yoshii
authors.affiliation: Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, MT 59840, USA. Electronic address: sbest@niaid.nih.gov.
authors.forename: Sonja M
authors.initials: SM
authors.lastname: Best
mesh_terms: D004150:Dipeptidases / Q000378:metabolism*; D004669:Encephalitis Viruses, Tick-Borne / Q000276:immunology*; D005347:Fibroblasts / Q000276:immunology; D054884:Host-Pathogen Interactions; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism*; D011485:Protein Binding; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism*; D015398:Signal Transduction; D017361:Viral Nonstructural Proteins / Q000378:metabolism; D014902:West Nile virus / Q000276:immunology*
chemical_list: C507964:IFNAR1 protein, human; D007370:Interferon Type I; C096041:NS5 protein, flavivirus; D017361:Viral Nonstructural Proteins; D053633:Receptor, Interferon alpha-beta; D004150:Dipeptidases; C022449:proline dipeptidase