Upregulates the expression levels of the PKR protein
When the PKR pathway is activated
Limits replication by an eIF2a-mediated block of translation
PKR requires a minimum of 33bp of perfect dsRNA for induction and around 80bp or more for optimal activation
EIF2a
Key part of ribosomal translation initiation
Viruses counteract PKR activity by using their own viral products or hijacking cellular proteins
PKR can act as a signal transducer in the IkB/NFkB pathway
Plays a role in the control of cellular processes such as apoptosis, cell growth, differentiation, and response to cellular stress other than viral infection
Protein kinase R (PKR)
Serine-threonine kinase encoded by the EIF2AK2 gene in humans, plays a major role in central cellular processes such as mRNA translation, transcriptional control, regulation of apoptosis and proliferation
PKR PAMPs
dsRNA
Synthetic structures ds-RNA with single-stranded tails and 5'triphosphate
HIV-1 TAR RNA
Either complete or incomplete influenza virus vRNP
Active PKR phosphorylates its substrate eIF2a, resulting in a block of translation
Activation of PKR during viral infection
Mediated by recognition of viral nucleic acid (dsRNA), inducing a structural rearrangement and bringing two PKR monomers into close proximity
Small amounts of PKR activation lead to the induction of type I interferons, resulting in the upregulation of interferon-stimulated genes, including PKR, creating a positive feedback loop
Contribution to antiviral immunity
PKR-mediated block of translation impairs efficient viral reproduction and spread
One mechanism viruses use to evade PKR response is hiding or sequestering dsRNA molecules
Mechanisms of viruses evading immune response
1. Hiding or Sequestering dsRNA molecules
2. PKR Degradation
3. Inhibition of PKR Dimerisation and Autophosphorylation
4. Interacting viral proteins
5. Acting downstream from eIf2a
Viral proteins acting downstream from eIf2a
NS4A protein from Dengue virus (DENV)
Viruses limiting dsRNA availability through degradation
Avian coronavirus
Inhibition of PKR Dimerisation and Autophosphorylation by viruses
Hantavirus
Interacting viral proteins inhibiting PKR kinase activation
E2 envelope protein of hepatitis C virus
K3L of VACV
PKR Degradation by viruses
Toscana virus (TOSV)
Rift valley fever virus (RVFV)
dsRNA sequestering viral proteins
MERS-CoV protein 4a
E3L protein of vaccinia virus (VACV)
NS1 Protein of Influenza
σ3 outer capsid protein of mammalian reovirus
Viruses evading immune response
Many viruses evolved to counteract PKR activity by using their own viral products or by hijacking cellular proteins