Virus-Induced Unfolded Protein Response Attenuates Antiviral Defenses via Phosphorylation-Dependent Degradation of the Type I Interferon Receptor

Jianghuai Liu, Wei Chun HuangFu, K. G Suresh Kumar, Juan Qian, James P. Casey, Robert B. Hamanaka, Christina Grigoriadou, Rafael Aldabe, J. Alan Diehl, Serge Y. Fuchs

Research output: Contribution to journalArticle

92 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)72-83
Number of pages12
JournalCell Host and Microbe
Volume5
Issue number1
DOIs
Publication statusPublished - Jan 22 2009
Externally publishedYes

Keywords

  • CELLBIO
  • MICROBIO
  • MOLIMMUNO

ASJC Scopus subject areas

  • Immunology and Microbiology(all)
  • Cancer Research
  • Molecular Biology

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    Liu, J., HuangFu, W. C., Kumar, K. G. S., Qian, J., Casey, J. P., Hamanaka, R. B., Grigoriadou, C., Aldabe, R., Diehl, J. A., & Fuchs, S. Y. (2009). Virus-Induced Unfolded Protein Response Attenuates Antiviral Defenses via Phosphorylation-Dependent Degradation of the Type I Interferon Receptor. Cell Host and Microbe, 5(1), 72-83. https://doi.org/10.1016/j.chom.2008.11.008