Induction of apoptosis by the dsRNA-dependent protein kinase (PKR): mechanism of action.

Abstract

Interferons are a family of cytokines that exerts antiviral, antitumor and immunomodulatory actions by inducing a complex set of proteins. One of the best known IFN-induced protein is the dsRNA-dependent protein kinase (PKR), that mediates both antiviral and anticellular activities. PKR inhibits translation initiation through the phosphorylation of the alpha subunit of the initiation factor eIF-2 (eIF-2 alpha) and also controls the activation of several transcription factors such as NF-kappa B, p53, or STATs. In addition, PKR mediates apoptosis induced by many different stimuli, such as treatment with LPS, TNF-alpha, viral infection, or serum starvation. The mechanism of apoptosis induction by PKR involves phosphorylation of eIF-2 alpha and activation of NF-kappa B. In this way, expression of different genes is regulated by PKR. Among the genes upregulated in response to PKR are Fas, Bax and p53. The pathway of PKR-induced apoptosis involves FADD activation of caspase 8 by a mechanism independent of Fas and TNFR. Since IFNs are used as drugs for different disorders such as viral infection and cancer, understanding the pathway of apoptosis induction triggered by PKR should be useful in the rational design of IFN therapies.