title: Virus-induced unfolded protein response attenuates antiviral defenses via phosphorylation-dependent degradation of the type I interferon receptor.
abstract: Phosphorylation-dependent ubiquitination and degradation of the IFNAR1 chain of the type I interferon (IFN) receptor is regulated by two different pathways, one of which is ligand independent. We report that this ligand-independent pathway is activated by inducers of unfolded protein responses (UPR), including viral infection, and that such activation requires the endoplasmic reticulum-resident protein kinase PERK. Upon viral infection, activation of this pathway promotes phosphorylation-dependent ubiquitination and degradation of IFNAR1, specifically inhibiting type I IFN signaling and antiviral defenses. Knockin of an IFNAR1 mutant insensitive to virus-induced turnover or conditional knockout of PERK prevented IFNAR1 degradation, whether UPR-induced or virus-induced, and restored cellular responses to type I IFN and resistance to viruses. These data suggest that specific activation of the PERK component of UPR can favor viral replication. Interfering with PERK-dependent IFNAR1 degradation could therefore contribute to therapeutic strategies against viral infections.
authors.affiliation: Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Jianghuai
authors.initials: J
authors.lastname: Liu
authors.forename: Wei-Chun
authors.initials: WC
authors.lastname: HuangFu
authors.forename: K G Suresh
authors.initials: KG
authors.lastname: Kumar
authors.forename: Juan
authors.initials: J
authors.lastname: Qian
authors.forename: James P
authors.initials: JP
authors.lastname: Casey
authors.forename: Robert B
authors.initials: RB
authors.lastname: Hamanaka
authors.forename: Christina
authors.initials: C
authors.lastname: Grigoriadou
authors.forename: Rafael
authors.initials: R
authors.lastname: Aldabe
authors.forename: J Alan
authors.initials: JA
authors.lastname: Diehl
authors.forename: Serge Y
authors.initials: SY
authors.lastname: Fuchs
mesh_terms: D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000821:virology*; D055879:Gene Knock-In Techniques; D017510:Protein Folding; D053633:Receptor, Interferon alpha-beta / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014780:Viruses / Q000276:immunology*; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D053633:Receptor, Interferon alpha-beta; D019892:eIF-2 Kinase; C508032:Ifnar1 protein, mouse