Virus-induced unfolded protein response attenuates antiviral defenses via phosphorylation-dependent degradation of the type I interferon receptor

Cell Host Microbe. 2009 Jan 22;5(1):72-83. doi: 10.1016/j.chom.2008.11.008.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum / virology*
  • Gene Knock-In Techniques
  • Protein Folding
  • Receptor, Interferon alpha-beta / antagonists & inhibitors*
  • Receptor, Interferon alpha-beta / genetics
  • Receptor, Interferon alpha-beta / immunology*
  • Receptor, Interferon alpha-beta / metabolism
  • Viruses / immunology*
  • eIF-2 Kinase / metabolism


  • Ifnar1 protein, mouse
  • Receptor, Interferon alpha-beta
  • PERK kinase
  • eIF-2 Kinase