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Cited by 818interferon and immune responsesEndoplasmic Reticulum Stress and DiseaseNF-κB Signaling Pathways

Impact of Protein Kinase PKR in Cell Biology: from Antiviral to Antiproliferative Action

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García, M. A., Gil, J., Ventoso, I., Guerra, S., Domingo, E., Rivas, C., Esteban, M.·2006·Microbiology and Molecular Biology Reviews
DOI 10.1128/mmbr.00027-06PMC PMC1698511
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Abstract

SUMMARY: The double-stranded RNA-dependent protein kinase PKR is a critical mediator of the antiproliferative and antiviral effects exerted by interferons. Not only is PKR an effector molecule on the cellular response to double-stranded RNA, but it also integrates signals in response to Toll-like receptor activation, growth factors, and diverse cellular stresses. In this review, we provide a detailed picture on how signaling downstream of PKR unfolds and what are the ultimate consequences for the cell fate. PKR activation affects both transcription and translation. PKR phosphorylation of the alpha subunit of eukaryotic initiation factor 2 results in a blockade on translation initiation. However, PKR cannot avoid the translation of some cellular and viral mRNAs bearing special features in their 5′ untranslated regions. In addition, PKR affects diverse transcriptional factors such as interferon regulatory factor 1, STATs, p53, activating transcription factor 3, and NF-κB. In particular, how PKR triggers a cascade of events involving IKK phosphorylation of IκB and NF-κB nuclear translocation has been intensively studied. At the cellular and organism levels PKR exerts antiproliferative effects, and it is a key antiviral agent. A point of convergence in both effects is that PKR activation results in apoptosis induction. The extent and strength of the antiviral action of PKR are clearly understood by the findings that unrelated viral proteins of animal viruses have evolved to inhibit PKR action by using diverse strategies. The case for the pathological consequences of the antiproliferative action of PKR is less understood, but therapeutic strategies aimed at targeting PKR are beginning to offer promising results.

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  • Five major effectors, eIF2a, FADD, p53, NF-κB and ATF-3, are implicated in mediating PKR-induced apoptosis.

    “At present, there are five major effectors, eIF2a, FADD, p53, NF-κB and ATF-3 implicated in mediating PKR-induced apoptosis [171].”

    From PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease (2009) · cites this paper as [171]

    The “Role of PKR Effectors in Apoptosis Induction” section implicates eIF-2α, NF-κB, ATF-3 and p53 in PKR-induced apoptosis. “Connections between PKR and the Apoptotic Machinery” says PKR-induced apoptosis mainly involves the FADD/caspase-8 pathway. The paper therefore supports a role for all five named factors, but does not identify them as a definitive set of five major effectors; it says “at least” four effectors are implicated and discusses FADD as part of the apoptotic machinery. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • PKR is implicated in infectious, inflammatory and ischemic pathology without cognitive decline.

    “PKR is not specific to neurodegenerative disease because it is also implied in infectious [61, 171], inflammatory [172, 173] and ischemic [171] pathology without cognitive decline.”

    From PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease (2009) · cites this paper as [171]

    The Introduction describes PKR as a defense mechanism against infection, and “PKR Mediates Apoptosis Induced by Different Stimuli” links it to pathogenic outcomes after viral infection. The cited paper’s discussion of ischemia/reperfusion injury concerns a stress that activates JNK; it does not establish PKR’s involvement in ischemic pathology or address whether cognitive decline is absent. Inflammatory pathology is attributed to other citations in the citing sentence. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Authors
García, M. A., Gil, J., Ventoso, I., Guerra, S., Domingo, E., Rivas, C., & Esteban, M.
Affiliations
  • Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología, Ciudad Universitaria Cantoblanco, 28049 Madrid, Spain
  • Hammersmith Hospital (GB)
  • Centro de Biología Molecular Severo Ochoa (ES)
  • Centro Nacional de Biotecnología (ES)
  • Universidad Complutense de Madrid (ES)
ORCID
Venue
Microbiology and Molecular Biology Reviews
Publisher
American Society for Microbiology
Published
2006-12
Volume
70
Issue
4
Pages
1032-1060
ISSN
  • 1092-2172 (ISSN-L)
  • 1098-5557
DOI
10.1128/mmbr.00027-06
PMC
PMC1698511
OpenAlex
W2108736984
Cited by
818
References
5
Citations by year
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FWCI
3.36
Type
journal article
Language
en
Open access
Licence
journals.asm.org/non-commercial-tdm-license (tdm)
Locations
  • Microbiology and Molecular Biology Reviews (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
Medical Research Council
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
Keywords
PKR, double-stranded RNA-dependent protein kinase, interferon signaling, antiviral response, antiproliferative activity, eIF2α phosphorylation, translation initiation, 5' untranslated region, IRF1, STAT, p53, NF-κB, IκB phosphorylation, apoptosis
MeSH terms
Animals, Antiviral Agents, Cells, Cell Biology, Humans, Interferons, Signal Transduction, eIF-2 Kinase

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