Activation of the Antiviral Kinase PKR and Viral Countermeasures

Abstract

The interferon-induced double-stranded (ds)RNA-dependent protein kinase (PKR) limits viral replication by an eIF2α-mediated block of translation. Although many negative-strand RNA viruses activate PKR, the responsible RNAs have long remained elusive, as dsRNA, the canonical activator of PKR, has not been detected in cells infected with such viruses. In this review we focus on the activating RNA molecules of different virus families, in particular the negative-strand RNA viruses. We discuss the recently identified non-canonical activators 5'-triphosphate RNA and the vRNP of influenza virus and give an update on strategies of selected RNA and DNA viruses to prevent activation of PKR.

Keywords: PKR; dsRNA; immune evasion; innate immunity; virus.

Figure 1.

Activation of PKR by different viral and synthetic RNAs. Latent PKR binds to (1) perfect dsRNA of viral or synthetic origin, (2) synthetic structured RNA with single stranded tails and a 5′triphosphate, (3) HIV-1 TAR RNA or (4) (possibly incomplete) influenza virus vRNP. This leads to dimerization and autophosphorylation of PKR. Active PKR then phosphorylates its substrate eIF2α, which results in a block of translation. PKR consists of two dsRNA-binding motifs (dsRBM1 + dsRBM2 in light green) and the N-terminal and C-terminal lobe of the kinase domain (dark green).