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 language | English |
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Pages (from-to) | 72-83 |
Number of pages | 12 |
Journal | Cell Host and Microbe |
Volume | 5 |
Issue number | 1 |
DOIs | |
Publication status | Published - Jan 22 2009 |
Externally published | Yes |
Keywords
- CELLBIO
- MICROBIO
- MOLIMMUNO
ASJC Scopus subject areas
- Parasitology
- Microbiology
- Virology