title: West Nile virus infection induces depletion of IFNAR1 protein levels.
abstract: Productive virus infection requires evasion, inhibition, or subversion of innate immune responses. West Nile virus (WNV), a human pathogen that can cause symptomatic infections associated with meningitis and encephalitis, inhibits the interferon (IFN) signal transduction pathway by preventing phosphorylation of Janus kinases and STAT transcription factors. Inhibition of the IFN signal cascade abrogates activation of IFN-induced genes, thus attenuating an antiviral response. We investigated the mechanism responsible for this inhibition and found that WNV infection prevents accumulation of the IFN-α receptor subunit 1 (IFNAR1). The WNV-induced depletion of IFNAR1 was conserved across multiple cell types. Our results indicated that expression of WNV nonstructural proteins resulted in activated lysosomal and proteasomal protein degradation pathways independent of the unfolded protein response (UPR). Furthermore, WNV infection did not induce serine phosphorylation, a modification on IFNAR1 that precedes its natural turnover. These data demonstrate that WNV infection results in a reduction of IFNAR1 protein through a non-canonical protein degradation pathway, and may participate in the inhibition of the IFN response.
authors.affiliation: Institute for Cancer Research , Fox Chase Cancer Center, Pittsburgh, PA 15261, USA. evansj2@pitt.edu
authors.forename: Jared D
authors.initials: JD
authors.lastname: Evans
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Crown
authors.forename: Ji A
authors.initials: JA
authors.lastname: Sohn
authors.forename: Christoph
authors.initials: C
authors.lastname: Seeger
mesh_terms: D000818:Animals; D002460:Cell Line; D054884:Host-Pathogen Interactions; D006801:Humans; D057131:Immune Evasion; D053633:Receptor, Interferon alpha-beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014902:West Nile virus / Q000276:immunology* / Q000472:pathogenicity*
chemical_list: C507964:IFNAR1 protein, human; D053633:Receptor, Interferon alpha-beta