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: 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
• Journal: Cell host & microbe (Cell Host Microbe) Vol. 5 Issue 1 Pg. 72-83 (Jan 22 2009) ISSN: 1934-6069 [Electronic] United States
• PMID: 19154989 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

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

Topics

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