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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dipeptidases / metabolism*
  • Encephalitis Viruses, Tick-Borne / immunology*
  • Fibroblasts / immunology
  • Host-Pathogen Interactions*
  • Humans
  • Interferon Type I / metabolism*
  • Protein Binding
  • Receptor, Interferon alpha-beta / metabolism*
  • Signal Transduction*
  • Viral Nonstructural Proteins / metabolism
  • West Nile virus / immunology*


  • IFNAR1 protein, human
  • Interferon Type I
  • NS5 protein, flavivirus
  • Viral Nonstructural Proteins
  • Receptor, Interferon alpha-beta
  • Dipeptidases
  • proline dipeptidase