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Deficient signaling in mice devoid of double-stranded RNA-dependent protein kinase
Y L Yang1, L F Reis, J Pavlovic
1Institut für Molekularbiologie I, Universität Zürich, Switzerland.
Abstract:
Double-stranded RNA-dependent protein kinase (PKR) has been implicated in interferon (IFN) induction, antiviral response and tumor suppression. We have generated mice devoid of functional PKR (Pkr%). Although the mice are physically normal and the induction of type I IFN genes by poly(I).poly(C) (pIC) and virus is unimpaired, the antiviral response induced by IFN-gamma and pIC was diminished. However, in embryo fibroblasts from Pkr knockout mice, the induction of type I IFN as well as the activation of NF-kappa B by pIC, were strongly impaired but restored by priming with IFN. Thus, PKR is not directly essential for responses to pIC, and a pIC-responsive system independent of PKR is induced by IFN. No evidence of the tumor suppressor activity of PKR was demonstrated.
Insights
Double-stranded RNA-dependent protein kinase (PKR) plays a role in antiviral responses. Mice lacking functional PKR showed impaired responses to certain immune stimuli, suggesting a complex regulatory role.
Area of Science:
- Immunology
- Molecular Biology
- Virology
Background:
- Double-stranded RNA-dependent protein kinase (PKR) is involved in interferon (IFN) induction, antiviral defense, and tumor suppression.
- The precise role of PKR in these processes requires further elucidation.
Purpose of the Study:
- To investigate the function of PKR in vivo by generating and analyzing mice lacking functional PKR (Pkr knockout mice).
- To assess the impact of PKR deficiency on type I IFN gene induction, antiviral responses, and NF-kappa B activation.
Main Methods:
- Generation of Pkr knockout mice.
- Stimulation with poly(I).poly(C) (pIC) and viruses to assess IFN induction.
- Analysis of antiviral responses induced by IFN-gamma and pIC.
- Examination of type I IFN induction and NF-kappa B activation in embryo fibroblasts, with and without IFN priming.
Main Results:
- Pkr knockout mice were physically normal, and type I IFN gene induction by pIC and virus was unimpaired.
- Antiviral responses induced by IFN-gamma and pIC were diminished in Pkr knockout mice.
- In Pkr knockout fibroblasts, pIC-induced type I IFN and NF-kappa B activation were impaired but restored by IFN priming.
- No evidence for tumor suppressor activity of PKR was observed.
Conclusions:
- PKR is not essential for direct responses to pIC; an IFN-induced, PKR-independent system mediates pIC responsiveness.
- PKR plays a significant role in IFN-gamma- and pIC-induced antiviral pathways.
- The study did not demonstrate tumor suppressor activity for PKR in this model.