Involvement of the double-stranded-RNA-dependent kinase PKR in interferon expression and interferon-mediated antiviral activity.
The signaling mechanisms responsible for the induced expression of interferon (IFN) genes by viral infection or double-stranded RNA (dsRNA) are not well understood. Here we investigate the role of the interferon-induced dsRNA-dependent protein kinase PKR in the regulation of IFN induction. Biological activities attributed to PKR include regulating protein synthesis, mediating IFN actions, and functioning as a possible tumor suppressor. Since binding of dsRNA is required for its activation, PKR has been considered as a candidate signal transducer for regulating IFN expression. To examine this role of PKR, loss-of-function phenotypes in stable transformants of promonocytic U-937 cells were achieved by two different strategies, overexpression of an antisense PKR transcript or a dominant negative PKR mutant gene. Both types of PKR-deficient cells were more permissive for viral replication than the control U-937 cells. As the result of PKR loss, they also showed impaired induction of IFN-alpha and IFN-beta genes in response to several inducers--specifically, encephalomyocarditis virus, lipopolysaccharide, and phorbol 12-myristate 13-acetate. Interestingly, while IFN-alpha induction by dsRNA was impaired in PKR-deficient cells, IFN-beta induction remained intact. Loss of PKR function also resulted in decreased antiviral activity as elicited by IFN-alpha and, to a greater extent, by IFN-gamma. These results implicate PKR in the regulation of several antiviral activities.
Der
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SD
Department of Pediatrics, San Francisco General Hospital, University of California 94110, USA.
Lau
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AS
D001483:Base Sequence; D016373:DNA, Antisense; D004686:Encephalomyocarditis virus / Q000187:drug effects / Q000254:growth & development*; D005786:Gene Expression Regulation; D006801:Humans; D016898:Interferon-alpha / Q000096:biosynthesis / Q000494:pharmacology; D016899:Interferon-beta / Q000096:biosynthesis / Q000494:pharmacology; D007372:Interferons / Q000096:biosynthesis* / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009000:Monocytes / Q000201:enzymology / Q000378:metabolism; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D013489:Suppression, Genetic; D014779:Virus Replication / Q000187:drug effects; D019892:eIF-2 Kinase
D016373:DNA, Antisense; D016898:Interferon-alpha; D016899:Interferon-beta; D007372:Interferons; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase