PrefaceSince the discovery of interferons (IFNs), considerable progress has been made in describing the nature of the cytokines themselves, the signalling components that direct the cell response and their antiviral activities. Gene targeting studies have distinguished four effector pathways of the IFNmediated antiviral response: the Mx GTPase pathway, the 2′-5′ oligoadenylate-synthetase-directed ribonuclease L pathway, the protein kinase R pathway and the ISG15 ubiquitin-like pathway. These effector pathways individually block viral transcription, degrade viral RNA, inhibit translation, and modify protein function to control all steps of viral replication. Ongoing research continues to expose additional activities for the effector proteins and has revealed unanticipated functions of the antiviral response. IntroductionInterferon (IFN) was discovered more than 50 years ago as an agent that inhibited the replication of influenza virus 1 . The IFN family of cytokines are now recognized as key components of the innate immune response and the first line of defence against virus infection. Accordingly, IFNs are currently used therapeutically, with the most noteworthy example, to combat Hepatitis C viral (HCV) infection, but also against a range of other disorders, including numerous malignancies and multiple sclerosis (recently reviewed 2 ).Three classes of IFN have been identified, designated types I to III, which are classified according to the receptor complex they signal through (Figure 1). Type II IFN consists of the single IFNγ gene product that binds the IFNGR receptor complex. IFNγ mediates broad immune responses to pathogens other than viruses. The more recently described type III IFNs include three IFNλ gene products that signal via the combined IFNLR1 and interleukin-10 receptor 2 (IL-10R2) receptors. To date little is known about the type III IFNs, although they are known to regulate the antiviral response and have been proposed to be the ancestral type I IFNs 3 . Type I IFNs, which in humans comprise 13 IFNα subtypes, IFNβ, IFNκ, IFNε, IFNo, IFNτ and IFNδ, engage the ubiquitously expressed IFNα receptor (IFNAR) complex that is composed of the two components, IFNAR1 and IFNAR2. The function of type I IFNs is well characterized and they are known to be essential for mounting a robust host response against viral infection. Accordingly, IFNAR-deficient mice have increased susceptibility to numerous viruses but maintain resistance to other microbial pathogens, such as Listeria monocytogenes 4, 5 . Similarly, humans with genetic defects in components of IFN signalling (STAT1, TYK2 or UNC93B) die of viral disease, with the defect in type I IFN (rather than IFNγ) signalling having the more significant role 6-9 .Binding of type I IFNs to IFNAR, with ensuing signal transduction, leads to the induction of more than 300 IFN-stimulated genes (ISGs) 10 . However, relatively few of these ISGs have been directly implicated in instigating the antiviral state. Instead, many of the gene products ISG15One of the most promi...

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The effects of interferons (IFNs) are mediated through the induction of around 2,000 IFN-stimulated gene (ISG) products. However, the majority of these ISGs do not directly instigate IFN-mediated states, such as the defining resistance to viral infection. Rather, most ISGs encode cell signaling molecules that enhance the responsiveness to pathogens, and systemically disseminate signals from localized sites of infection. Relatively few IFN effector proteins have been well characterized. The protein kinase R (PKR) is one of the first and best characterized of these effector molecules. PKR mediates responses via phosphorylation of protein substrates and promotes signal transduction pathways to maintain homeostasis, mediate immune responses, and, upon sustained activation, promote apoptosis. As a number of reviews have dealt with PKR-dependent resistance to virus, this review will cover broader roles ascribed to PKR and the mechanism(s) by which PKR exerts its effects.