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

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.

eIF2A mediates translation of hepatitis C viral mRNA under stress conditions

“…PKR, one of the several eIF2a kinases and a component of the interferonmediated antiviral response, participates in the innate immune response that protects host cells from virus infections by blocking translation of viral mRNAs (Samuel, 2001;Garcia et al, 2006). Many viruses have evolved various strategies to nullify this cellular response (Garcia et al, 2006).…”

Roles of the translationally controlled tumour protein (TCTP) and the double-stranded RNA-dependent protein kinase, PKR, in cellular stress responses

“…PKR is activated by binding to double-stranded RNA formed during viral replication; it phosphorylates the a-subunit of translation factor eIF2, resulting in inhibition of protein synthesis (Barber, 2005;Garcia et al, 2007). PKR has also been implicated in many additional cellular stress responses and corresponding signal transduction pathways, including the nuclear factor-kB and p38-mitogen-activated protein kinase pathways (reviewed by Barber, 2005;Garcia et al, 2006Garcia et al, , 2007. A major role for PKR has recently emerged in the control of apoptosis, following activation of the tumour-suppressor p53 pathway (Yoon et al, 2009).…”

“…A major role for PKR has recently emerged in the control of apoptosis, following activation of the tumour-suppressor p53 pathway (Yoon et al, 2009). Inhibition of protein synthesis through eIF2a phosphorylation plays a considerable part in PKR activity (Scheuner et al, 2006;Lee et al, 2007), but other pathways are most likely also involved (Garcia et al, 2006).…”

Molecular cloning, characterization and expression analysis of the PKZ gene in rare minnow Gobiocypris rarus

“…This prevents viral replication and inhibits normal cell ribosome function, killing both the virus and the host cell if the response is active for a sufficient amount of time [6]. PKR cannot block the translation of some cellular and viral mRNAs bearing special features in their 5 0 untranslated regions [7]. PKR also affects diverse transcriptional factors such as interferon regulatory factor 1, STATs, p53, activating transcription factor 3, and NF-B [8,9].…”

“…PKR also affects diverse transcriptional factors such as interferon regulatory factor 1, STATs, p53, activating transcription factor 3, and NF-B [8,9]. 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 diverse strategies to inhibit PKR action [7,10]. Knock-out mouse studies confirmed a role for PKR in antiviral innate immunity [11].…”