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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    • "RNA activated/dependent protein kinase (PKR) is a serine threonine kinase that can directly couple to the metabolic pathway due to its catalytic activity and has a role in pathogen recognition [2]. PKR is activated by a number of signals, such as high cholesterol diet [3], pathogens, irradiation, heme limitation [4] [5] [6] [7] [8] [9] [10] endoplasmic reticulum (ER) stress and mechanical stress [11]. PKR contains two dsRNA binding domains, one at its N-terminal and the other at its C-terminal [4–5, 12]. "
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    ABSTRACT: Metabolic syndrome greatly increases the risk for developing metabolic and cardiovascular disorders and has reached epidemic proportions globally. Despite recent advances in medical science, scientific understandings on the root mechanisms of metabolic syndrome are still not fully understood, and such insufficient knowledge contributes to the relative lack of effective treatments for such diseases. Protein Kinase R (PKR) is a serine threonine kinase activated during various stress conditions. Activation of PKR can increase reactive oxygen product generation, cause oxidative stress and inflammation. In this review we discuss the potential role of PKR in metabolic syndrome, pathways activated by it and the interrelationship between pathways activated, modes of propagation if one of the pathways is inhibited or activated. Specific and effective inhibitors of PKR are being developed and can become potential treatment for metabolic syndrome and prevent many diseases.
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    • "Productive interaction requires residues from both dsRBM1 and -2 as well as the linker that joins them (Kim et al. 2006). One of the most unique features of PKR is its selectivity for dsRNA: Single-stranded polynucleotides , dsDNA, and DNA–RNA hybrids are not capable of high-affinity interaction (Gale and Katze 1998). Structures of a single dsRBM from proteins other than PKR in complex with perfectly duplexed dsRNA indicate that approximately 1.5 turns (∼16 bp) of the A-form RNA helix comprising consecutive minor-major-minor grooves are recognized and that contacts are mediated primarily through the 2 ′ -hydroxyl groups of the ribose sugar, explaining the observed selectivity (Bycroft et al. 1995; Kharrat et al. 1995; Ryter and Schultz 1998; Ramos et al. 2000; Gan et al. 2006; Stefl et al. 2010). "
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    ABSTRACT: In humans, the double-stranded RNA (dsRNA)-activated protein kinase (PKR) is expressed in late stages of the innate immune response to viral infection by the interferon pathway. PKR consists of tandem dsRNA binding motifs (dsRBMs) connected via a flexible linker to a Ser/Thr kinase domain. Upon interaction with viral dsRNA, PKR is converted into a catalytically active enzyme capable of phosphorylating a number of target proteins that often results in host cell translational repression. A number of high-resolution structural studies involving individual dsRBMs from proteins other than PKR have highlighted the key features required for interaction with perfectly duplexed RNA substrates. However, viral dsRNA molecules are highly structured and often contain deviations from perfect A-form RNA helices. By use of small-angle X-ray scattering (SAXS), we present solution conformations of the tandem dsRBMs of PKR in complex with two imperfectly base-paired viral dsRNA stem-loops; HIV-1 TAR and adenovirus VA(I)-AS. Both individual components and complexes were purified by size exclusion chromatography and characterized by dynamic light scattering at multiple concentrations to ensure monodispersity. SAXS ab initio solution conformations of the individual components and RNA-protein complexes were determined and highlight the potential of PKR to interact with both stem and loop regions of the RNA. Excellent agreement between experimental and model-based hydrodynamic parameter determination heightens our confidence in the obtained models. Taken together, these data support and provide a framework for the existing biochemical data regarding the tolerance of imperfectly base-paired viral dsRNA by PKR.
    RNA 01/2013; 19(3). DOI:10.1261/rna.035931.112 · 4.94 Impact Factor
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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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