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J. Biol. Chem., Vol. 276, Issue 12, 8951-8957, March 23, 2001
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From the Induction of interferon-
IRF3 and IRF7 Phosphorylation in Virus-infected Cells Does Not
Require Double-stranded RNA-dependent Protein Kinase R or
I
B Kinase but Is Blocked by Vaccinia Virus E3L Protein*
,,
Department of Pathology and Kaplan
Comprehensive Cancer Center, Molecular Oncology and Immunology Program,
New York University School of Medicine, New York, New York 10016 and
the ¶ Mount Sinai School of Medicine of New York University,
New York, New York 10029
(IFN) gene
expression in virus-infected cells requires phosphorylation-induced
activation of the transcription factors IRF3 and IRF7. However, the
kinase(s) that targets these proteins has not been identified. Using a
combined pharmacological and genetic approach, we found that none of
the kinases tested was responsible for IRF phosphorylation in cells infected with Newcastle disease virus (NDV). Although the
broad-spectrum kinase inhibitor staurosporine potently blocked IRF3 and
-7 phosphorylation, inhibitors for protein kinase C, protein kinase A,
MEK, SAPK, IKK, and protein kinase R (PKR) were without effect. Both
I
B kinase and PKR have been implicated in IFN induction, but cells genetically deficient in IB kinase, PKR, or the
PKR-related genes PERK, IRE1, or
GCN2 retained the ability to phosphorylate IRF7 and induce
IFN. Interestingly, PKR mutant cells were defective for
response to double-stranded (ds) RNA but not to virus infection, suggesting that dsRNA is not the only activating viral component. Consistent with this notion, protein synthesis was required for IRF7
phosphorylation in virus-infected cells, and the kinetics of
phosphorylation and viral protein production were similar. Despite
evidence for a lack of involvement of dsRNA and PKR, vaccinia virus E3L
protein, a dsRNA-binding protein capable of inhibiting PKR, was an
effective IRF3 and -7 phosphorylation inhibitor. These results suggest
that a novel cellular protein that is activated by viral products in
addition to dsRNA and is sensitive to E3L inhibition is responsible for
IRF activation and reveal a novel mechanism for the anti-IFN effect of
E3L distinct from its inhibition of PKR.
*
This work was supported in part by National Institutes of
Health Grants AI28900, AI46503, and AI46954 and by a fellowship from
the Arthritis Foundation.The costs of publication of this article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of
Pathology, MSB 556, New York University School of Medicine, 550 First Ave., New York, NY 10016. Tel.: 212-263-8192; Fax: 212-263-8211; E-mail: levyd01@med.nyu.edu.
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