PKR in Innate Immunity, Cancer, and Viral Oncolysis

Abstract

The mammalian innate immune system provides a first line of defense against microbial pathogens and also serves to activate an antigen specific acquired immune program. Key components of innate immunity are the interferons (IFNs), a family of related cytokines with potent antimicrobial and immuno-modulatory activities. The IFNs exert their effects through the induction of numerous genes, one of which is the double-stranded RNA-dependent protein kinase (PKR), a pivotal antiviral protein found in most human cells. Following activation by double stranded (ds) RNAs produced during viral replication, PKR phosphorylates the alpha-subunit of eukaryotic translation initiation factor (eIF) 2, causing a severe inhibititon of cellular and viral protein synthesis. Phosphorylation of eIF2alpha and consequent inhibition of protein synthesis is a major cell growth checkpoint utilized by at least three other kinases, in addition to PKR, following exposure to such cellular stresses as amino acid deprivation and the presence of misfolded proteins in the endoplasmic reticulum. Indeed, it has been demonstrated that disruption of the eIF2alpha checkpoint can lead to the transformation of immortalized rodent and human cells, plausibly by increasing the protein synthesis rates of proto-oncogenes. Further, it has been shown that disregulation of the eIF2alpha checkpoint and consequent permissiveness to virus infection may be a common occurrence in tumorigenic mammalian cell lines. These findings hav…