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.
Highlights
Unit Hepacivirus and Innate Immunity, Department Virology, Institut Pasteur, 28 rue du Dr Roux, Tel.: +33-145-68-87-77; Fax: +33-140-61-30-12
GCN2 form an inactive dimer through its region homologous to histidyl-tRNA synthetase (HisRS) and becomes activated, by change of conformation, when this domain binds uncharged tRNA, allowing its N-terminal ring finger and WD repeat domain (RWD) to bind GCN1 required for its function
Accumulation of phosphorylated PKR in the nucleus is considered as a response to cellular stress and it has been linked to some pathologies, such as leukemic development [22,23] and sporadic Alzheimer disease [24,25] or Creutzfeldt-Jakob disease (CJD) [26]
Summary
PKR is a 551 amino acid protein [1] that can be linked to two different families of proteins: The eIF2α-kinase family and the dsRNA-binding protein family. GCN2 form an inactive dimer through its region homologous to histidyl-tRNA synthetase (HisRS) and becomes activated, by change of conformation, when this domain binds uncharged tRNA, allowing its N-terminal ring finger and WD repeat domain (RWD) to bind GCN1 required for its function. It contains a Ribosomal Binding site (RB) at its. After binding of the first DRBD to dsRNA, binding of the second DRBD stabilizes the dsRNA/PKR complex and opens the conformation of PKR This allows PKR dimerization through the N-lobe of its kinase domain (blue).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
