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 Activation of NF-κB by PKR

Various factors, including viral infections, lead to the increased expression and secretion of the cytokine, interferon gamma (IFN-g), from host cells. IFN-g induces the dsRNA-dependent serine/threonine protein kinase R (PKR). PKR, also known as P1 Kinase; P1/eIF-2a Kinase; p68; p67; DAI, ds1, or TIK, is a central mediator of cellular response to viral infection and/or environmental stress that determines whether a cell does or does not enter apoptosis. The primary immediate upstream effectors of PKR activation are dsRNA or PACT (RAX). Double stranded RNA and PACT (RAX) signal the PKR signaling cascade(s) that a viral or an environmental threat is occurring, respectively. Signals to PKR can mediate both kinase-dependent and kinase-independent activities, which appear to be pro-apoptotic and anti-apoptotic, respectively.

Early response PKR activation involves a kinase-independent process that leads to the release of NFkB, probably p50/RelA (aka p50/p65), from IkB, which sends an anti-apoptotic signal. Prolonged signaling to PKR activates its kinase activity which leads to the phosphorylation of the protein initiation factor 2alpha (eIF2a) and IkB kinase complex (IKK). Phosphorylation of eIF2a inhibits the initiation of RNA translation. Inhibition of protein synthesis affects the level of critical proteins, such as the IkB, which has a short half-life. The loss of IkB may lead to the release of NFkB p50/cRel which is generally pro-apoptotic. Activation of IkB kinase complex also leads to the phosphorylation of IkB and the release of NF-kBs.