dsRNA-Dependent Protein Kinase PKR and its Role in Stress, Signaling and HCV Infection

Abstract

The double-stranded RNA-dependent protein kinase PKR plays multiple roles in cells, in response to different stress situations. As a member of the interferon (IFN)‑Stimulated Genes, PKR was initially recognized as an actor in the antiviral action of IFN, due to its ability to control translation, through phosphorylation, of the alpha subunit of eukaryotic initiation factor 2 (eIF2α). As such, PKR participates in the generation of stress granules, or autophagy and a number of viruses have designed strategies to inhibit its action. However, PKR deficient mice resist most viral infections, indicating that PKR may play other roles in the cell other than just acting as an antiviral agent. Indeed, PKR regulates several signaling pathways, either as an adapter protein and/or using its kinase activity. Here we review the role of PKR as an eIF2α kinase, its participation in the regulation of the NF-κB, p38MAPK and insulin pathways, and we focus on its role during infection with the hepatitis C virus (HCV). PKR binds the HCV IRES RNA, cooperates with some functions of the HCV core protein and may represent a target for NS5A or E2. Novel data points out for a role of PKR as a pro-HCV agent, both as an adapter protein and as an eIF2α-kinase, and in cooperation with the di-ubiquitin-like protein ISG15. Developing pharmaceutical inhibitors of PKR may help in resolving some viral infections as well as stress-related damages.

Integrated Stress Response Signaling Pathways Induced by Supraphysiological Concentrations of Thyroid Hormone Inhibit Viral Replication

“…In this study, we have shown that T3 induces activation of PKR, eIF2α phosphorylation, SG formation, and induction of ER stress pathways. Because all these T3-induced pathways are also the hallmarks of a strong host-mediated antiviral response, 12,18,22,23,41 we tested the ability of T3 to inhibit the replication of an RNA virus, VSV, in HeLa cells. For VSV infection, cells were pretreated with DMSO or different concentrations of T3 and infected with VSV-GFP in the presence of DMSO or T3, and viral replication was analyzed by fluorescent microscopy, RT-PCR, and Western blotting.…”

“…Activation of PKR is known to phosphorylate eIF2α, resulting in the translational shutdown and activation of stress pathways. 22,23,36 To explore whether T3 affects the phosphorylation of eIF2α, HeLa cells were treated with DMSO or T3 or transfected with Poly IC in the presence or absence of T3 and analyzed by immunofluorescence (IF) using antibodies to phospho-eIF2α. T3 alone, like Poly IC, induced the phosphorylation of eIF2α and its translocation to nuclear compartment ( Fig.…”

“…Like PERK, activated PKR also phosphorylates the subunit of translation initiation factor eIF2, resulting in translational shutdown and inhibition of viral replication. 22,23 Thus, PKR plays a central role as an ISG that links IFN response pathways to ISR during viral infections.…”

Translation factors and ribosomal proteins control tumor onset and progression: how?

“…However, as mentioned before, specific mRNAs containing a short uORF in front of a main ORF are de-repressed when eIF2a is phosphorylated, and are translated through a mechanism known as reinitiation. 70 Four kinases can phosphorylate eIF2a: PERK, activated by the UPR, 71 gcn2, activated (mainly) by amino acid deprivation, 72 PKR, activated by ds RNA 73 and HRI, activated by heme. 70 The role of eIF2a phosphorylation in cancer cells is dual and context-dependent, possibly due to the multiple mechanisms ending in eIF2a phosphorylation.…”

Potential role for snoRNAs in PKR activation during metabolic stress

“…It is an IFN-induced kinase found in a latent form in most cells (3) and was initially identified as an antiviral protein involved in innate immunity (4). It is generally accepted that PKR activation is triggered by viral doublestranded RNA (dsRNA) during infection (5).…”