Double-stranded RNA-activated protein kinase mediates virus-induced apoptosis: A new role for an old actor

Abstract

Eukaryotic viruses and their multicellular hosts have coevolved complex interrelationships to permit virus reproduction without destruction of the host. The IFN-induced cellular antiviral response is the first line of defense against viral infection within an animal host. On viral infection, the expression of IFN is induced at the transcriptional level. The IFN is secreted to protect adjacent cells from secondary infection, thereby limiting viral spread. Type I IFNs are composed of the different types of IFN-α that are produced in leukocytes and the IFN-β that is produced in fibroblasts and epithelial cells. Type I IFNs bind to their receptors and activate a signaling cascade that culminates in the transcriptional induction of at least 30 genes (1). Two of these genes encode latent enzymes requiring activation by binding to double-stranded (ds)RNA that is produced as a replication intermediate in the viral life cycle. First, latent 2′-5′-oligoadenylate synthetase is activated by dsRNA to increase synthesis of 2′-5′ oligoadenylates that are required to activate 2′-5′-A-dependent RNase L (2). Activated RNase L nonspecifically degrades single-stranded RNAs and thus limits virus production. Second, the dsRNA-activated protein kinase (PKR), the most well characterized IFN-induced gene product, mediates the antiviral actions of type I IFNs. In studies reported in this issue of PNAS, Lau and coworkers (3) show that reduction in PKR level acts to delay cell death and thereby converts a lytic infection by encephalomyocarditis virus (EMCV) into a persistent infection. These studies as well as those from other laboratories support the idea that viral pathogenesis may be mediated by PKR-induced cell death and suggest that modification of PKR function in vivo may be a feasible approach to influence viral pathogenesis. In addition, the study presents a model system that may be applied to study mechanisms responsible for the establishment of persistent infections for other viruses such as HIV and hepatitis C virus.