The Role of Protein Kinase R in the Interferon Response

There is a growing evidence describing a decline in adaptive homeostasis in aging-related diseases affecting the central nervous system (CNS), many of which are characterized by the appearance of non-native protein aggregates. One signaling pathway that allows cell adaptation is the integrated stress response (ISR), which senses stress stimuli through four kinases. ISR activation promotes translational arrest through the phosphorylation of the eukaryotic translation initiation factor 2 alpha (eIF2α) and the induction of a gene expression program to restore cellular homeostasis. However, depending on the stimulus, ISR can also induce cell death. One of the ISR sensors is the double-stranded RNA-dependent protein kinase [protein kinase R (PKR)], initially described as a viral infection sensor, and now a growing evidence supports a role for PKR on CNS physiology. PKR has been largely involved in the Alzheimer’s disease (AD) pathological process. Here, we reviewed the antecedents supporting the role of PKR on the efficiency of synaptic transmission and cognition. Then, we review PKR’s contribution to AD and discuss the possible participation of PKR as a player in the neurodegenerative process involved in aging-related pathologies affecting the CNS.

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Tumour necrosis factor α up-regulates protein kinase R (PKR)-activating protein (PACT) and increases phosphorylation of PKR and eukaryotic initiation factor 2-α in articular chondrocytes

Biochemical Society Transactions ◽

10.1042/bst0300886 ◽

2002 ◽

Vol 30 (6) ◽

pp. 886-889 ◽

Cited By ~ 13

Author(s):

S. J. Gilbert ◽

V. C. Duance ◽

D. J. Mason

Keyword(s):

Protein Kinase ◽

Tumour Necrosis ◽

Cartilage Degradation ◽

Initiation Factor ◽

Tumour Necrosis Factor Α ◽

Protein Kinase R ◽

Initiation Factor 2 ◽

Factor Α ◽

Necrosis Factor

Our previous analysis of the genes regulated in cartilage at the onset of spontaneous osteoarthritis in the guinea pig knee revealed up-regulation of the gene for protein kinase R (PKR)-activating protein (PACT), which encodes the cellular activator of the protein kinase, PKR. PACT and PKR are upstream components of a number of signal transduction and gene transcription pathways used by pro-inflammatory cytokines. We have investigated the role of PACT and PKR in articular cartilage degradation using cytokine treatment of bovine primary chondrocytes and cartilage explants. Tumour necrosis factor α increased expression of PACT protein after 3 h of treatment. Furthermore, increased phosphorylation of PKR and eukaryotic initiation factor 2-α was observed. The known role of PKR in cytokine-induced signalling pathways, together with our data showing cytokine regulation of PACT and PKR in chondrocytes, reveals a novel mechanism of cartilage degradation that may be important in the pathogenesis of arthritic diseases.

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The role of host eIF2α in viral infection

Virology Journal ◽

10.1186/s12985-020-01362-6 ◽

2020 ◽

Vol 17 (1) ◽

Cited By ~ 3

Author(s):

Yuanzhi Liu ◽

Mingshu Wang ◽

Anchun Cheng ◽

Qiao Yang ◽

Ying Wu ◽

...

Keyword(s):

Protein Synthesis ◽

Protein Kinase ◽

Viral Infection ◽

Infection Process ◽

Host Protein ◽

Main Body ◽

Protein Kinase R ◽

Viral Protein Synthesis ◽

Eif2α Phosphorylation

Abstract Background eIF2α is a regulatory node that controls protein synthesis initiation by its phosphorylation or dephosphorylation. General control nonderepressible-2 (GCN2), protein kinase R-like endoplasmic reticulum kinase (PERK), double-stranded RNA (dsRNA)-dependent protein kinase (PKR) and heme-regulated inhibitor (HRI) are four kinases that regulate eIF2α phosphorylation. Main body In the viral infection process, dsRNA or viral proteins produced by viral proliferation activate different eIF2α kinases, resulting in eIF2α phosphorylation, which hinders ternary tRNAMet-GTP-eIF2 complex formation and inhibits host or viral protein synthesis. The stalled messenger ribonucleoprotein (mRNP) complex aggregates under viral infection stress to form stress granules (SGs), which encapsulate viral RNA and transcription- and translation-related proteins, thereby limiting virus proliferation. However, many viruses have evolved a corresponding escape mechanism to synthesize their own proteins in the event of host protein synthesis shutdown and SG formation caused by eIF2α phosphorylation, and viruses can block the cell replication cycle through the PERK-eIF2α pathway, providing a favorable environment for their own replication. Subsequently, viruses can induce host cell autophagy or apoptosis through the eIF2α-ATF4-CHOP pathway. Conclusions This review summarizes the role of eIF2α in viral infection to provide a reference for studying the interactions between viruses and hosts.

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Role of protein kinase R in double-stranded RNA-induced expression of nitric oxide synthase in human astroglia

FEBS Letters ◽

10.1016/s0014-5793(04)00302-3 ◽

2004 ◽

Vol 563 (1-3) ◽

pp. 223-228 ◽

Cited By ~ 33

Author(s):

Corey J Auch ◽

Ramendra N Saha ◽

Faruk G Sheikh ◽

Xiaojuan Liu ◽

Bertram L Jacobs ◽

...

Keyword(s):

Nitric Oxide ◽

Protein Kinase ◽

Nitric Oxide Synthase ◽

Protein Kinase R ◽

Induced Expression ◽

Double Stranded Rna ◽

Oxide Synthase

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Andes Virus Nucleocapsid Protein Interrupts Protein Kinase R Dimerization To Counteract Host Interference in Viral Protein Synthesis

Journal of Virology ◽

10.1128/jvi.02347-14 ◽

2014 ◽

Vol 89 (3) ◽

pp. 1628-1639 ◽

Cited By ~ 12

Author(s):

Zekun Wang ◽

Mohammad A. Mir

Keyword(s):

Protein Kinase ◽

Viral Infection ◽

Virus Replication ◽

Nucleocapsid Protein ◽

Viral Proteins ◽

Antiviral Response ◽

Interferon Response ◽

Protein Kinase R ◽

Andes Virus ◽

Infected Cells

ABSTRACTPathogenic hantaviruses delay the type I interferon response during early stages of viral infection. However, the robust interferon response and induction of interferon-stimulated genes observed during later stages of hantavirus infection fail to combat the virus replication in infected cells. Protein kinase R (PKR), a classical interferon-stimulated gene product, phosphorylates the eukaryotic translation initiation factor eIF2α and causes translational shutdown to create roadblocks for the synthesis of viral proteins. The PKR-induced translational shutdown helps host cells to establish an antiviral state to interrupt virus replication. However, hantavirus-infected cells do not undergo translational shutdown and fail to establish an antiviral state during the course of viral infection. In this study, we showed for the first time that Andes virus infection induced PKR overexpression. However, the overexpressed PKR was not active due to a significant inhibition of autophosphorylation. Further studies revealed that Andes virus nucleocapsid protein inhibited PKR dimerization, a critical step required for PKR autophosphorylation to attain activity. The studies reported here establish a hantavirus nucleocapsid protein as a new PKR inhibitor. These studies provide mechanistic insights into hantavirus resistance to the host interferon response and solve the puzzle of the lack of translational shutdown observed in hantavirus-infected cells. The sensitivity of hantavirus replication to PKR has likely imposed a selective evolutionary pressure on hantaviruses to evade the PKR antiviral response for survival. We envision that evasion of the PKR antiviral response by NP has likely helped hantaviruses to exist during evolution and to survive in infected hosts with a multifaceted antiviral defense.IMPORTANCEProtein kinase R (PKR), a versatile antiviral host factor, shuts down the translation machinery upon activation in virus-infected cells to create hurdles for the manufacture of viral proteins. The studies reported here reveal that the hantavirus nucleocapsid protein counteracts the PKR antiviral response by inhibiting PKR dimerization, which is required for its activation. We report the discovery of a new PKR inhibitor whose expression in hantavirus-infected cells prevents the PKR-induced host translational shutdown to ensure the continuous synthesis of viral proteins required for efficient virus replication.

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Role of protein kinase R in the killing of Leishmania major by macrophages in response to neutrophil elastase and TLR4 via TNFα and IFNβ

The FASEB Journal ◽

10.1096/fj.13-245126 ◽

2014 ◽

Vol 28 (7) ◽

pp. 3050-3063 ◽

Cited By ~ 23

Author(s):

Marilia S. Faria ◽

Tereza C. Calegari‐Silva ◽

Aislan de Carvalho Vivarini ◽

Jeremy C. Mottram ◽

Ulisses Gazos Lopes ◽

...

Keyword(s):

Protein Kinase ◽

Neutrophil Elastase ◽

Leishmania Major ◽

Protein Kinase R

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181 Role of interferon-inducible adenosine deaminase that acts on RNA 1 in the inhibition of the protein kinase R activation during HIV-1 infection

Cytokine ◽

10.1016/j.cyto.2008.07.243 ◽

2008 ◽

Vol 43 (3) ◽

pp. 282

Author(s):

Guerline Clerzius ◽

Jean-François Gélinasa ◽

Aïcha Daher ◽

Eliane Meurs ◽

Anne Gatignol

Keyword(s):

Protein Kinase ◽

Adenosine Deaminase ◽

Protein Kinase R ◽

Hiv 1

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Suppression of NYVAC Infection in HeLa Cells Requires RNase L but Is Independent of Protein Kinase R Activity

Journal of Virology ◽

10.1128/jvi.02576-15 ◽

2015 ◽

Vol 90 (4) ◽

pp. 2135-2141 ◽

Cited By ~ 1

Author(s):

Mercedes Fernández-Escobar ◽

José Luis Nájera ◽

Sara Baldanta ◽

Dolores Rodriguez ◽

Michael Way ◽

...

Keyword(s):

Gene Expression ◽

Protein Kinase ◽

Hela Cells ◽

Rnase L ◽

Abortive Infection ◽

Protein Kinase R ◽

Viral Spread ◽

Viral Genes ◽

Cell Components

Protein kinase R (PKR) and RNase L are host cell components that function to contain viral spread after infections. In this study, we analyzed the role of both proteins in the abortive infection of human HeLa cells with the poxvirus strain NYVAC, for which an inhibition of viralA27LandB5Rgene expression is described. Specifically, the translation of these viral genes is independent of PKR activation, but their expression is dependent on the RNase L activity.

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