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 |
|---|---|
| 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 |
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Keywords
- CELLBIO
- MICROBIO
- MOLIMMUNO
ASJC Scopus subject areas
- Immunology and Microbiology(all)
- Cancer Research
- Molecular Biology
Cite this
Virus-Induced Unfolded Protein Response Attenuates Antiviral Defenses via Phosphorylation-Dependent Degradation of the Type I Interferon Receptor. / Liu, Jianghuai; HuangFu, Wei Chun; Kumar, K. G Suresh; Qian, Juan; Casey, James P.; Hamanaka, Robert B.; Grigoriadou, Christina; Aldabe, Rafael; Diehl, J. Alan; Fuchs, Serge Y.
In: Cell Host and Microbe, Vol. 5, No. 1, 22.01.2009, p. 72-83.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Virus-Induced Unfolded Protein Response Attenuates Antiviral Defenses via Phosphorylation-Dependent Degradation of the Type I Interferon Receptor
AU - Liu, Jianghuai
AU - HuangFu, Wei Chun
AU - Kumar, K. G Suresh
AU - Qian, Juan
AU - Casey, James P.
AU - Hamanaka, Robert B.
AU - Grigoriadou, Christina
AU - Aldabe, Rafael
AU - Diehl, J. Alan
AU - Fuchs, Serge Y.
PY - 2009/1/22
Y1 - 2009/1/22
N2 - 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.
AB - 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.
KW - CELLBIO
KW - MICROBIO
KW - MOLIMMUNO
UR - http://www.scopus.com/inward/record.url?scp=58249084172&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=58249084172&partnerID=8YFLogxK
U2 - 10.1016/j.chom.2008.11.008
DO - 10.1016/j.chom.2008.11.008
M3 - Article
VL - 5
SP - 72
EP - 83
JO - Cell Host and Microbe
JF - Cell Host and Microbe
SN - 1931-3128
IS - 1
ER -