Molecular Mechanisms of Interferon Resistance Mediated by Viral-Directed Inhibition of PKR, the Interferon-Induced Protein Kinase

Pharmacology [?] Therapeutics (Impact Factor: 9.72). 05/1998; 78(1):29-46. DOI: 10.1016/S0163-7258(97)00165-4


The interferon (IFN)-induced cellular antiviral response is the first line of defense against viral infection within an animal host. In order to establish a productive infection, eukaryotic viruses must first overcome the IFN-induced blocks imposed on viral replication. The double-stranded RNA-activated protein kinase (PKR) is a key component mediating the antiviral actions of IFN. This IFN-induced protein kinase can restrict viral replication through its ability to phosphorylate the protein synthesis initiation factor eukaryotic initiation factor-2 α-subunit and reduce levels of viral protein synthesis. Viruses, therefore, must block the function of PKR in order to avoid these deleterious antiviral effects associated with PKR activity. Indeed, many viruses have developed effective measures to repress PKR activity during infection. This review will focus primarily on an overview of the different molecular mechanisms employed by these viruses to meet a common goal: the inhibition of PKR function, uncompromised viral protein synthesis, and unrestricted virus replication. The past few years have seen exciting new advances in this area. Rather unexpectedly, this area of research has benefited from the use of the yeast system to study PKR. Other recent advances include studies on PKR regulation by the herpes simplex viruses and data from our laboratory on the medically important hepatitis C viruses. We speculate that IFN is ineffective as a therapeutic agent against hepatitis C virus because the virus can effectively repress PKR function. Finally, we will discuss briefly the future directions of this PKR field. pharmacol. ther. 78(1):29–46, 1998.

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    • "The level of double-stranded (ds) RNA-dependent protein kinase (PKR) is enhanced by IFN treatment, however catalytic activity of PKR requires dsRNA. When IFN-treated cells are infected by virus, dsRNA, produced as a by-product of viral replication, activates PKR, and the activated PKR inactivates eukaryotic translation initiation factor (eIF) 2á by phosphorylation [3]. Another antiviral protein 2′–5′ oligoadenylate synthetase (OAS) is also induced to express by IFN. "
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    ABSTRACT: Retinoic acid inducible gene I (RIG-I)-like receptors (RLRs) function as cytoplasmic sensors for viral RNA to initiate antiviral responses including type I interferon (IFN) production. It has been unclear how RIG-I encounters and senses viral RNA. To address this issue, we examined intracellular localization of RIG-I in response to viral infection using newly generated anti-RIG-I antibody. Immunohistochemical analysis revealed that RLRs localized in virus-induced granules containing stress granule (SG) markers together with viral RNA and antiviral proteins. Because of similarity in morphology and components, we termed these aggregates antiviral stress granules (avSGs). Influenza A virus (IAV) deficient in non-structural protein 1 (NS1) efficiently generated avSGs as well as IFN, however IAV encoding NS1 produced little. Inhibition of avSGs formation by removal of either the SG component or double-stranded RNA (dsRNA)-dependent protein kinase (PKR) resulted in diminished IFN production and concomitant enhancement of viral replication. Furthermore, we observed that transfection of dsRNA resulted in IFN production in an avSGs-dependent manner. These results strongly suggest that the avSG is the locus for non-self RNA sensing and the orchestration of multiple proteins is critical in the triggering of antiviral responses.
    PLoS ONE 08/2012; 7(8):e43031. DOI:10.1371/journal.pone.0043031 · 3.23 Impact Factor
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    • "Another effector function of PKR is activation of transcription factor IRF3, which leads to the expression of IFN β and inhibition of virus replication [14], [15]. Being such a crucial component of the host innate immune system, PKR is tightly regulated by cellular inhibitors [16] and very often targeted by viral proteins [17]–[20]. For example, the non-structural protein 1 (NS1) of influenza virus directly binds to PKR and prevents its activation [21], [22]. "
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    ABSTRACT: Double-stranded RNA dependent protein kinase (PKR) is a key regulator of the anti-viral innate immune response in mammalian cells. PKR activity is regulated by a 58 kilo Dalton cellular inhibitor (P58(IPK)), which is present in inactive state as a complex with Hsp40 under normal conditions. In case of influenza A virus (IAV) infection, P58(IPK) is known to dissociate from Hsp40 and inhibit PKR activation. However the influenza virus component responsible for PKR inhibition through P58(IPK) activation was hitherto unknown. Human heat shock 40 protein (Hsp40) was identified as an interacting partner of Influenza A virus nucleoprotein (IAV NP) using a yeast two-hybrid screen. This interaction was confirmed by co-immunoprecipitation studies from mammalian cells transfected with IAV NP expressing plasmid. Further, the IAV NP-Hsp40 interaction was validated in mammalian cells infected with various seasonal and pandemic strains of influenza viruses. Cellular localization studies showed that NP and Hsp40 co-localize primarily in the nucleus. During IAV infection in mammalian cells, expression of NP coincided with the dissociation of P58(IPK) from Hsp40 and decrease PKR phosphorylation. We observed that, plasmid based expression of NP in mammalian cells leads to decrease in PKR phosphorylation. Furthermore, inhibition of NP expression during influenza virus replication led to PKR activation and concomitant increase in eIF2α phosphorylation. Inhibition of NP expression also led to reduced IRF3 phosphorylation, enhanced IFN β production and concomitant reduction of virus replication. Taken together our data suggest that NP is the viral factor responsible for P58(IPK) activation and subsequent inhibition of PKR-mediated host response during IAV infection. Our findings demonstrate a novel role of IAV NP in inhibiting PKR-mediated anti-viral host response and help us understand P58(IPK) mediated inhibition of PKR activity during IAV infection.
    PLoS ONE 06/2011; 6(6):e20215. DOI:10.1371/journal.pone.0020215 · 3.23 Impact Factor
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    • "This activated form of PKR phosphorylates the alpha subunit of eukaryotic initiation factor 2 (eIF2α), which in turn leads to translational arrest. Indeed, reports have suggested a critical role for PKR in mediating ds-RNA-induced apoptosis in cells [70]. "
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    ABSTRACT: Influenza viruses comprise a major class of human respiratory pathogens, responsible for causing morbidity and mortality worldwide. Influenza A virus, due to its segmented RNA genome, is highly subject to mutation, resulting in rapid formation of variants. During influenza infection, viral proteins interact with host proteins and exploit a variety of cellular pathways for their own benefit. Influenza virus inhibits the synthesis of these cellular proteins and facilitates expression of its own proteins for viral transcription and replication. Infected cell pathways are hijacked by an array of intracellular signaling cascades such as NF-κB signaling, PI3K/Akt pathway, MAPK pathway, PKC/PKR signaling and TLR/RIG-I signaling cascades. This review presents a research update on the subject and discusses the impact of influenza viral infection on these cell signaling pathways.
    Medical science monitor: international medical journal of experimental and clinical research 06/2011; 17(6):RA148-54. DOI:10.12659/MSM.881801 · 1.43 Impact Factor
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