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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 Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
that in humans is encoded by the ''EIF2AK2''
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
. PKR protects against
viral infection A viral disease (or viral infection) occurs when an organism's body is invaded by pathogenic viruses, and infectious virus particles (virions) attach to and enter susceptible cells. Structural Characteristics Basic structural characteristics, s ...
s.


Mechanism of action

Protein kinase-R is activated by
double-stranded RNA Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydr ...
(dsRNA), introduced to the cells by a viral infection. PKR can also be activated by the protein
PACT A pact, from Latin ''pactum'' ("something agreed upon"), is a formal agreement between two or more parties. In international relations, pacts are usually between two or more sovereign states. In domestic politics, pacts are usually between two or ...
or by heparin. PKR contains an
N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
dsRNA binding domain (dsRBD) and a
C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
kinase In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...
domain, that gives it
pro-apoptotic Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
(cell-killing) functions. The dsRBD consists of two tandem copies of a conserved double stranded RNA binding motif, dsRBM1 and dsRBM2. PKR is induced by
interferon Interferons (IFNs, ) 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 the ...
in a latent state. Binding to dsRNA is believed to activate PKR by inducing
dimerization A dimer () (''wikt:di-, di-'', "two" + ''-mer'', "parts") is an oligomer consisting of two monomers joined by bonds that can be either strong or weak, Covalent bond, covalent or Intermolecular force, intermolecular. Dimers also have significant im ...
and subsequent auto-
phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
reactions. In situations of viral infection, the dsRNA created by viral replication and gene expression binds to the
N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
domain, activating the protein. Once active, PKR is able to phosphorylate the eukaryotic translation initiation factor eIF2α. This inhibits further cellular mRNA translation, thereby preventing viral protein synthesis. Since ElF2α is involved in common initiation translation via an AUG codon, the alternative non-AUG initiation takes place instead. An example of mRNAs using non-AUG initiation are mRNAs for the heat shock proteins. Active PKR is also able to mediate the activation of the transcription factor NFkB, by phosphorylating its inhibitory subunit, IkB. Activated NFkB up-regulates the expression of Interferon cytokines, which work to spread the antiviral signal locally. Active PKR is also able to activate tumor suppressor
PP2A Protein phosphatase 2 (PP2), also known as PP2A, is an enzyme that in humans is encoded by the ''PPP2CA'' gene. The PP2A heterotrimeric protein phosphatase is ubiquitously expressed, accounting for a large fraction of phosphatase activity in eu ...
which regulates the cell cycle and the metabolism. Through complex mechanisms, active PKR is also able to induce cellular
apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
, to prevent further viral spread.


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. The PKR pathway leads to a stress response through activation of other stress pathways such as
JNK 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 ...
, p38, NFkB,
PP2A Protein phosphatase 2 (PP2), also known as PP2A, is an enzyme that in humans is encoded by the ''PPP2CA'' gene. The PP2A heterotrimeric protein phosphatase is ubiquitously expressed, accounting for a large fraction of phosphatase activity in eu ...
and phosphorylation of eIF2α. ER stress caused by excess of unfolded proteins leads to inflammatory responses. PKR contributes to this response by interacting with several inflammatory kinases such as IKK, JNK, ElF2α, insulin receptor and others. This metabolically activated inflammatory complex is called metabolic inflammasome or metaflammasome. PKR also participates in the mitochondrial unfolded protein response (UPRmt). Here, PKR is induced via the transcription factor AP-1 and activated independently of PACT. In this context, PKR has been shown to be relevant to intestinal inflammation.


Viral defense

Viruses have developed many mechanisms to counteract the PKR mechanism. It may be done by
Decoy dsRNA A decoy (derived from the Dutch ''de'' ''kooi'', literally "the cage" or possibly ''ende kooi'', " duck cage") is usually a person, device, or event which resembles what an individual or a group might be looking for, but it is only meant to lu ...
, degradation, hiding of viral
dsRNA Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
, dimerization block, dephosphorylation of substrate or by a
pseudosubstrate A decoy (derived from the Dutch ''de'' ''kooi'', literally "the cage" or possibly ''ende kooi'', " duck cage") is usually a person, device, or event which resembles what an individual or a group might be looking for, but it is only meant to lu ...
. For instance,
Epstein–Barr virus The Epstein–Barr virus (EBV), formally called ''Human gammaherpesvirus 4'', is one of the nine known human herpesvirus types in the herpes family, and is one of the most common viruses in humans. EBV is a double-stranded DNA virus. It is b ...
(EBV) uses the gene EBER1 to produce decoy dsRNA. This leads to cancers such as
Burkitt's lymphoma Burkitt lymphoma is a cancer of the lymphatic system, particularly B lymphocytes found in the germinal center. It is named after Denis Parsons Burkitt, the Irish surgeon who first described the disease in 1958 while working in equatorial Africa. ...
,
Hodgkin's disease Hodgkin lymphoma (HL) is a type of lymphoma, in which cancer originates from a specific type of white blood cell called lymphocytes, where multinucleated Reed–Sternberg cells (RS cells) are present in the patient's lymph nodes. The condition wa ...
,
nasopharyngeal carcinoma Nasopharyngeal carcinoma (NPC), or nasopharynx cancer, is the most common cancer originating in the nasopharynx, most commonly in the postero-lateral nasopharynx or pharyngeal recess ( fossa of Rosenmüller), accounting for 50% of cases. NPC occurs ...
and various
leukemias Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or '' ...
.


Memory and learning

PKR
knockout mice A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or "knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...
or inhibition of PKR in mice enhances memory and learning. *


Neuronal degeneration disease

First report in 2002 has been shown that
immunohistochemical Immunohistochemistry (IHC) is the most common application of immunostaining. It involves the process of selectively identifying antigens (proteins) in cells of a tissue section by exploiting the principle of antibodies binding specifically to ant ...
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 Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
(AD), suggesting the link between PKR and AD. Additionally, many of these neurons were also immunostained with an antibody for phosphorylated
Tau protein The tau proteins (abbreviated from tubulin associated unit) are a group of six highly soluble protein isoforms produced by alternative splicing from the gene ''MAPT'' (microtubule-associated protein tau). They have roles primarily in maintaining ...
. Activated PKR was specifically found in the cytoplasm and nucleus, as well as co-localized with neuronal apoptotic markers. Further studies have assessed the levels of PKR in blood and
cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates. CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the bra ...
(CSF) of AD patients and controls. The result of an analysis of the concentrations of total and phosphorylated PKR (pPKR) in
peripheral blood mononuclear cell A peripheral blood mononuclear cell (PBMC) is any peripheral blood cell having a round nucleus. These cells consist of lymphocytes (T cells, B cells, NK cells) and monocytes, whereas erythrocytes and platelets have no nuclei, and granulocytes (neu ...
s (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. 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". 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 Beta-secretase 1, also known as beta-site amyloid precursor protein cleaving enzyme 1, beta-site APP cleaving enzyme 1 (BACE1), membrane-associated aspartic protease 2, memapsin-2, aspartyl protease 2, and ASP2, is an enzyme that in humans is enco ...
(β-site APP Cleaving Enzyme) expression in Alzheimer Disease patients. 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 Herpes simplex virus 1 and 2 (HSV-1 and HSV-2), also known by their taxonomical names ''Human alphaherpesvirus 1'' and '' Human alphaherpesvirus 2'', are two members of the human ''Herpesviridae'' family, a set of viruses that produce viral inf ...
(HSV) or oxidative stress can both increase BACE1 expression through activation of PKR-eIF2a pathway. 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
endosome Endosomes are a collection of intracellular sorting organelles in eukaryotic cells. They are parts of endocytic membrane transport pathway originating from the trans Golgi network. Molecules or ligands internalized from the plasma membrane can ...
s in AD. 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 rab 5 overactivation. βCTF recruits
APPL1 Adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1 (APPL1), or DCC-interacting protein 13-alpha (DIP13alpha), is a protein that in humans is encoded by the ''APPL1'' gene. APPL1 contains several key interactory domain ...
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. A protein phosphatase-2A inhibitor (PP2A inhibitor) –
Okadaic acid Okadaic acid, C44H68O13, is a toxin produced by several species of dinoflagellates, and is known to accumulate in both marine sponges and shellfish. One of the primary causes of diarrhetic shellfish poisoning, okadaic acid is a potent inhibitor of ...
(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 Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
and nuclear translocation, contributing to neuronal death.
Glycogen Synthase Kinase Aβ (GSK-3β)
is responsible for tau phosphorylation and controls several cellular functions including apoptosis. Another study demonstrated that
tunicamycin Tunicamycin is a mixture of homologous nucleoside antibiotics that inhibits the UDP-HexNAc: polyprenol-P HexNAc-1-P family of enzymes. In eukaryotes, this includes the enzyme GlcNAc phosphotransferase (GPT), which catalyzes the transfer of N- ...
or Aβ treatment can induce PKR activation in human
neuroblastoma Neuroblastoma (NB) is a type of cancer that forms in certain types of nerve tissue. It most frequently starts from one of the adrenal glands but can also develop in the neck, chest, abdomen, or spine. Symptoms may include bone pain, a lump in the ...
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 Small interfering RNA (siRNA), sometimes known as short interfering RNA or silencing RNA, is a class of double-stranded RNA at first non-coding RNA molecules, typically 20-24 (normally 21) base pairs in length, similar to miRNA, and operating wi ...
. PKR could represent a crucial signaling point relaying stress signals to neuronal pathways by interacting with
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...
or indirectly controlling GSK3β activation, leading to cellular degeneration in AD.


Fetal alcohol syndrome

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


Interactions

Protein kinase R has been shown to
interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with: *
ASK1 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 ...
, *
DNAJC3 DnaJ homolog subfamily C member 3 is a protein that in humans is encoded by the ''DNAJC3'' gene. Function The protein encoded by this gene contains multiple tetratricopeptide repeat (TPR) motifs as well as the highly conserved J domain found in ...
, *
ILF3 Interleukin enhancer-binding factor 3 is a protein that in humans is encoded by the ''ILF3'' gene. Function Nuclear factor of activated T-cells (NFAT) is a transcription factor required for T-cell expression of interleukin 2. NFAT binds to a s ...
, *
METAP2 Methionine aminopeptidase 2 is an enzyme that in humans is encoded by the ''METAP2'' gene. Methionine aminopeptidase 2, a member of the dimetallohydrolase family, is a cytosolic metalloenzyme that catalyzes the hydrolytic removal of N-terminal m ...
, *
P53 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...
, *
PPP1CA Serine/threonine-protein phosphatase PP1-alpha catalytic subunit is an enzyme that in humans is encoded by the ''PPP1CA'' gene. Function The protein encoded by this gene is one of the three catalytic subunits of protein phosphatase 1 (PP1). PP ...
, *
PRKRA 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 pro ...
, *
STAT1 Signal transducer and activator of transcription 1 (STAT1) is a transcription factor which in humans is encoded by the ''STAT1'' gene. It is a member of the STAT protein family. Function All STAT molecules are phosphorylated by receptor associa ...
, and *
TARBP2 RISC-loading complex subunit TARBP2 is a protein that in humans is encoded by the ''TARBP2'' gene. Function HIV-1, the causative agent of acquired immunodeficiency syndrome (AIDS), contains an RNA genome that produces a chromosomally integrate ...
.


References


Further reading

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