Protein kinase R

Last updated
EIF2AK2
EIF2AK2 protein.png 6d3k orange adp green mg.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases EIF2AK2 , EIF2AK1, PKR, PPP1R83, PRKR, eukaryotic translation initiation factor 2 alpha kinase 2, LEUDEN, DYT33
External IDs OMIM: 176871 MGI: 1353449 HomoloGene: 48134 GeneCards: EIF2AK2
EC number 2.7.10.2
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001135651
NM_001135652
NM_002759

NM_011163

RefSeq (protein)

NP_001129123
NP_001129124
NP_002750

NP_035293

Location (UCSC) Chr 2: 37.1 – 37.16 Mb Chr 17: 79.16 – 79.19 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Protein kinase RNA-activated also known as protein kinase R (PKR), interferon-induced, double-stranded RNA-activated protein kinase, or eukaryotic translation initiation factor 2-alpha kinase 2 (EIF2AK2) is an enzyme that in humans is encoded by the EIF2AK2 gene on chromosome 2. [5] [6] PKR is a serine/tyrosine kinase that is 551 amino acids long. [7]

Contents

PKR is inducible by various mechanisms of stress and protects against viral infections. [8] It also has a role in several signaling pathways. [9] [10]

Mechanism of action

Protein kinase-R is activated by double-stranded RNA (dsRNA), introduced to the cells by a viral infection. [9] In situations of viral infection, the dsRNA created by viral replication and gene expression binds to the N-terminal domain, activating the protein. [9] PKR activation via dsRNA is length dependent, requiring the dsRNA to be 30 bp in length to bind to PKR molecules. [9] However, excess dsRNA can diminish activation of PKR. [9] Binding to dsRNA is believed to activate PKR by inducing dimerization of the kinase domains and subsequent auto-phosphorylation reactions. [9] PKR can also be activated by the protein PACT via phosphorylation of S287 on its M3 domain. [11] The promoter region of PKR has interferon-stimulated response elements to which Type I interferons (IFN) bind to induce the transcription of PKR genes. [11] [12] Some research suggests that PKR can be stimulated by heat shock proteins, heparin, growth factors, bacterial infection, pro-inflammatory cytokines, reactive oxygen species, DNA damage, mechanical stress, and excess nutrient intake. [11]

Once active, PKR is able to phosphorylate the eukaryotic translation initiation factor eIF2α. [11] This inhibits further cellular mRNA translation, thereby preventing viral protein synthesis. [10] Overall, this leads to apoptosis of virally infected cells to prevent further viral spread. PKR can also induce apoptosis in bacterial infection by responding to LPS and proinflammatory cytokines. [10] Apoptosis can also occur via PKR activation of the FADD and caspase signaling pathway. [12]

PKR also has pro-inflammatory functions, as it can mediate the activation of the transcription factor NF-kB, by phosphorylating its inhibitory subunit, IkB. [12] This leads to the expression of adhesion molecules and transcription factors that activate them, which induce inflammation responses such as the secretion of pro-inflammatory cytokines. [11] PKR also activates several mitogen-activated protein kinases (MAPK) to lead to inflammation. [12]

To balance the effects of apoptosis and inflammation, PKR has regulatory functions. Active PKR is also able to activate tumor suppressor PP2A which regulates the cell cycle and the metabolism. [13] There is also evidence that PKR is autophagic as a regulatory mechanism. [12]

Figure showing the different signaling pathways that activated PKR plays a role in. Most results of these pathways help in fighting off viral infection and regulating the immune response, conferring PKR with apoptotic and pro-inflammatory functionality. Figure of PKR signalling pathways.png
Figure showing the different signaling pathways that activated PKR plays a role in. Most results of these pathways help in fighting off viral infection and regulating the immune response, conferring PKR with apoptotic and pro-inflammatory functionality.

PKR stress pathway

PKR is in the center of cellular response to different stress signals such as pathogens, lack of nutrients, cytokines, irradiation, mechanical stress, or ER stress. [11] The PKR pathway leads to a stress response through activation of other stress pathways such as JNK, p38, NFkB, PP2A and phosphorylation of eIF2α. [10] ER stress caused by excess of unfolded proteins leads to inflammatory responses. [14] PKR contributes to this response by interacting with several inflammatory kinases such as IKK, JNK, ElF2α, insulin receptors and others. [14] This metabolically activated inflammatory complex is called metabolic inflammasome or metaflammasome. [15] [16] Via the JNK signaling pathway, PKR also plays a role in insulin resistance, diabetes, and obesity by phosphorylating IRS1. [17] Inhibiting PKR in mice led to lower inflammation in adipose tissues, increased sensitivity to insulin, and amelioration of diabetic symptoms. [17] PKR also participates in the mitochondrial unfolded protein response (UPRmt). [18] Here, PKR is induced via the transcription factor AP-1 and activated independently of PACT. [18] In this context, PKR has been shown to be relevant to intestinal inflammation. [18]

Viral defense

Viruses have developed many mechanisms to counteract the PKR mechanism. It may be done by Decoy dsRNA, degradation, hiding of viral dsRNA, dimerization block, dephosphorylation of substrate or by a pseudosubstrate.

For instance, Epstein–Barr virus (EBV) uses the gene EBER1 to produce decoy dsRNA. This leads to cancers such as Burkitt's lymphoma, Hodgkin's disease, nasopharyngeal carcinoma and various leukemias.

Viral defense mechanisms against PKR
Defense typeVirusMolecule
Decoy dsRNA Adenovirus VAI RNA
Epstein–Barr virus EBER
HIV TAR
PKR degradation Poliovirus 2Apro
Hide viral dsRNA Vaccinia virus E3L
Reovirus σ3
Influenza virus NS1
Dimerization blockInfluenza virus p58IPK
Hepatitis C virus NS5A
Pseudosubstrate Vaccinia virus K3L
HIV Tat
Dephosphorylation of substrate Herpes simplex virus ICP34.5

Memory and learning

PKR knockout mice or inhibition of PKR in mice enhances memory and learning. [19]

Neuronal degeneration disease

First report in 2002 has been shown that immunohistochemical marker for phosphorylated PKR and eIF2α was displayed positively in degenerating neurons in the hippocampus and the frontal cortex of patients with Alzheimer's disease (AD), suggesting the link between PKR and AD. Additionally, many of these neurons were also immunostained with an antibody for phosphorylated Tau protein. [20] Activated PKR was specifically found in the cytoplasm and nucleus, as well as co-localized with neuronal apoptotic markers. [21] Further studies have assessed the levels of PKR in blood and cerebrospinal fluid (CSF) of AD patients and controls. The result of an analysis of the concentrations of total and phosphorylated PKR (pPKR) in peripheral blood mononuclear cells (PBMCs) in 23 AD patients and 19 control individuals showed statistically significant increased levels of the ratio of phosphorylated PKR/PKR in AD patients compared with controls. [22] Assessments of CSF biomarkers, such as Aβ1-42, Aβ1-40, Tau, and phosphorylated Tau at threonine 181, have been a validated use in clinical research and in routine practice to determine whether patients have CSF abnormalities and AD brain lesions. A study found that "total PKR and pPKR concentrations were elevated in AD and amnestic mild cognitive impairment subjects with a pPKR value (optical density units) discriminating AD patients from control subjects with a sensitivity of 91.1% and a specificity of 94.3%. Among AD patients, total PKR and pPKR levels correlate with CSF p181tau levels. Some AD patients with normal CSF Aß, T-tau, or p181tau levels had abnormal total PKR and pPKR levels". [23] It was concluded that the PKR-eIF2α pro-apoptotic pathway could be involved in neuronal degeneration that leads to various neuropathological lesions as a function of neuronal susceptibility.

PKR and beta amyloid

Activation of PKR can cause accumulation of amyloid β-peptide (Aβ) via de-repression of BACE1 (β-site APP Cleaving Enzyme) expression in Alzheimer Disease patients. [24] Normally, the 5′ untranslated region (5′ UTR) in the BACE1 promoter would fundamentally inhibit the expression of BACE1 gene. However, BACE1 expression can be activated by phosphorylation of eIF2a, which reverses the inhibitory effect exerted by BACE1 5′ UTR. Phosphorylation of eIF2a is triggered by activation of PKR. Viral infection such as herpes simplex virus (HSV) or oxidative stress can both increase BACE1 expression through activation of PKR-eIF2a pathway. [25]

In addition, the increased activity of BACE1 could also lead to β-cleaved carboxy-terminal fragment of β-Amyloid precursor protein (APP-βCTF) induced dysfunction of endosomes in AD. [26] Endosomes are highly active β-Amyloid precursor protein (APP) processing sites, and endosome abnormalities are associated with upregulated expression of early endosomal regulator, Rab5. These are the earliest known disease-specific neuronal response in AD. Increased activity of BACE1 leads to synthesis of the APP-βCTF. An elevated level of βCTF then causes Rab5 overactivation. βCTF recruits APPL1 to rab5 endosomes, where it stabilizes active GTP-Rab5, leading to pathologically accelerated endocytosis, endosome swelling and selectively impaired axonal transport of Rab5 endosomes.

PKR and Tau phosphorylation

It is reported earlier that phosphorylated PKR could co-localize with phosphorylated Tau protein in affected neurons. [27] [20] A protein phosphatase-2A inhibitor (PP2A inhibitor) – okadaic acid (OA) – is known to increase tau phosphorylation, Aβ deposition and neuronal death. It is studied that OA also induces PKR phosphorylation and thus, eIF2a phosphorylation. eIF2a phosphorylation then induces activation of transcription factor 4 (ATF4), which induces apoptosis and nuclear translocation, contributing to neuronal death. [28]

Glycogen synthase kinase 3β (GSK-3β) is responsible for tau phosphorylation and controls several cellular functions including apoptosis. Another study demonstrated that tunicamycin or Aβ treatment can induce PKR activation in human neuroblastoma cells and can trigger GSK3β activation, as well as tau phosphorylation. They found that in AD brains, both activated PKR and GSK3β co-localize with phosphorylated tau in neurons. In SH-SY5Y cell cultures, tunicamycin and Aβ(1-42) activate PKR, which then can modulate GSK-3β activation and induce tau phosphorylation, apoptosis. All these processes are attenuated by PKR inhibitors or PKR siRNA. PKR could represent a crucial signaling point relaying stress signals to neuronal pathways by interacting with transcription factor or indirectly controlling GSK3β activation, leading to cellular degeneration in AD. [29]

Fetal alcohol syndrome

PKR also mediates ethanol-induced protein synthesis inhibition and apoptosis which is linked to fetal alcohol syndrome. [30]

Interactions

Protein kinase R has been shown to interact with:

Related Research Articles

<span class="mw-page-title-main">Interferon</span> Signaling proteins released by host cells in response to the presence of pathogens

Interferons are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten their anti-viral defenses.

The NS1 influenza protein (NS1) is a viral nonstructural protein encoded by the NS gene segments of type A, B and C influenza viruses. Also encoded by this segment is the nuclear export protein (NEP), formally referred to as NS2 protein, which mediates the export of influenza virus ribonucleoprotein (RNP) complexes from the nucleus, where they are assembled.

c-Jun N-terminal kinases Chemical compounds

c-Jun N-terminal kinases (JNKs), were originally identified as kinases that bind and phosphorylate c-Jun on Ser-63 and Ser-73 within its transcriptional activation domain. They belong to the mitogen-activated protein kinase family, and are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock. They also play a role in T cell differentiation and the cellular apoptosis pathway. Activation occurs through a dual phosphorylation of threonine (Thr) and tyrosine (Tyr) residues within a Thr-Pro-Tyr motif located in kinase subdomain VIII. Activation is carried out by two MAP kinase kinases, MKK4 and MKK7, and JNK can be inactivated by Ser/Thr and Tyr protein phosphatases. It has been suggested that this signaling pathway contributes to inflammatory responses in mammals and insects.

<span class="mw-page-title-main">ASK1</span> Protein-coding gene in the species Homo sapiens

Apoptosis signal-regulating kinase 1 (ASK1) also known as mitogen-activated protein kinase 5 (MAP3K5) is a member of MAP kinase family and as such a part of mitogen-activated protein kinase pathway. It activates c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases in a Raf-independent fashion in response to an array of stresses such as oxidative stress, endoplasmic reticulum stress and calcium influx. ASK1 has been found to be involved in cancer, diabetes, rheumatoid arthritis, cardiovascular and neurodegenerative diseases.

<span class="mw-page-title-main">ILF3</span> Protein-coding gene in the species Homo sapiens

Interleukin enhancer-binding factor 3 is a protein that in humans is encoded by the ILF3 gene.

<span class="mw-page-title-main">DNA damage-inducible transcript 3</span> Human protein and coding gene

DNA damage-inducible transcript 3, also known as C/EBP homologous protein (CHOP), is a pro-apoptotic transcription factor that is encoded by the DDIT3 gene. It is a member of the CCAAT/enhancer-binding protein (C/EBP) family of DNA-binding transcription factors. The protein functions as a dominant-negative inhibitor by forming heterodimers with other C/EBP members, preventing their DNA binding activity. The protein is implicated in adipogenesis and erythropoiesis and has an important role in the cell's stress response.

<span class="mw-page-title-main">EIF2S1</span> Protein-coding gene in the species Homo sapiens

Eukaryotic translation initiation factor 2 subunit 1 (eIF2α) is a protein that in humans is encoded by the EIF2S1 gene.

<span class="mw-page-title-main">PRKRA</span> Protein-coding gene in the species Homo sapiens

Protein kinase, interferon-inducible double stranded RNA dependent activator, also known as interferon-inducible double stranded RNA-dependent protein kinase activator A or Protein ACTivator of the interferon-induced protein kinase (PACT) is a protein that in humans is encoded by the PRKRA gene. PACT heterodimerizes with and activates protein kinase R. PRKRA mutations have been linked to a rare form of dystonia parkinsonism.

<span class="mw-page-title-main">DNAJC3</span> Human protein and coding gene

DnaJ homolog subfamily C member 3 is a protein that in humans is encoded by the DNAJC3 gene.

<span class="mw-page-title-main">MDA5</span> Mammalian protein found in Homo sapiens

MDA5 is a RIG-I-like receptor dsRNA helicase enzyme that is encoded by the IFIH1 gene in humans. MDA5 is part of the RIG-I-like receptor (RLR) family, which also includes RIG-I and LGP2, and functions as a pattern recognition receptor capable of detecting viruses. It is generally believed that MDA5 recognizes double stranded RNA (dsRNA) over 2000nts in length, however it has been shown that whilst MDA5 can detect and bind to cytoplasmic dsRNA, it is also activated by a high molecular weight RNA complex composed of ssRNA and dsRNA. For many viruses, effective MDA5-mediated antiviral responses are dependent on functionally active LGP2. The signaling cascades in MDA5 is initiated via CARD domain. Some observations made in cancer cells show that MDA5 also interacts with cellular RNA is able to induce an autoinflammatory response.

<span class="mw-page-title-main">EIF2A</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">PRKRIR</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Cyclin-dependent kinase 5</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">MAPK10</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">C16 (drug)</span> Chemical compound

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<span class="mw-page-title-main">Viral strategies for immune response evasion</span>

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Further reading