Protein kinase R

Eukaryotic translation initiation factor 2-alpha kinase 2
250px NMR structure of the double stranded RNA binding domain of EIF2AK2 based on PDB: 1qu6​.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1QU6, 2A19, 2A1A, 3UIU
Identifiers
Symbols	EIF2AK2 ; EIF2AK1; PKR; PPP1R83; PRKR
External IDs	OMIM: 176871 MGI: 1353449 HomoloGene: 48134 ChEMBL: 5785 GeneCards: EIF2AK2 Gene
EC number	2.7.10.2, 2.7.11.1
Gene ontology Molecular function • double-stranded RNA binding • protein kinase activity • protein serine/threonine kinase activity • eukaryotic translation initiation factor 2alpha kinase activity • non-membrane spanning protein tyrosine kinase activity • protein binding • ATP binding • protein phosphatase type 2A regulator activity • poly(A) RNA binding Cellular component • nucleus • cytoplasm • cytosol • ribosome • membrane • perinuclear region of cytoplasm Biological process • activation of MAPKK activity • positive regulation of cytokine production • transcription, DNA-templated • translation • protein phosphorylation • negative regulation of cell proliferation • response to virus • regulation of translational initiation by eIF2 alpha phosphorylation • negative regulation of translation • peptidyl-tyrosine phosphorylation • modulation by virus of host morphology or physiology • modulation by virus of host process • viral life cycle • evasion or tolerance by virus of host immune response • endoplasmic reticulum unfolded protein response • positive regulation of chemokine production • positive regulation of stress-activated MAPK cascade • negative regulation of osteoblast proliferation • regulation of protein phosphatase type 2A activity • response to interferon-alpha • negative regulation of apoptotic process • negative regulation of viral genome replication • innate immune response • protein autophosphorylation • positive regulation of NF-kappaB transcription factor activity • defense response to virus • regulation of NLRP3 inflammasome complex assembly • positive regulation of NIK/NF-kappaB signaling • regulation of hematopoietic progenitor cell differentiation • regulation of hematopoietic stem cell proliferation • regulation of hematopoietic stem cell differentiation Sources: Amigo / QuickGO
RNA expression pattern
File:PBB GE EIF2AK2 204211 x at tn.png
File:PBB GE EIF2AK2 213294 at tn.png
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	5610	19106
Ensembl	ENSG00000055332	ENSMUSG00000024079
UniProt	P19525	Q03963
RefSeq (mRNA)	NM_001135651	NM_011163
RefSeq (protein)	NP_001129123	NP_035293
Location (UCSC)	Chr 2: 37.1 – 37.16 Mb	Chr 17: 78.85 – 78.88 Mb
PubMed search	[1]	[2]

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.

PKR protects against viral infections.

Mechanism of action

Protein kinase-R is activated by double-stranded RNA (dsRNA), introduced to the cells by a viral infection. PKR can also be activated by the protein PACT or by heparin. PKR contains an N-terminal dsRNA binding domain (dsRBD) and a C-terminal kinase domain, that gives it pro-apoptotic (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 in a latent state. Binding to dsRNA is believed to activate PKR by inducing dimerization and subsequent auto-phosphorylation reactions. In situations of viral infection, the dsRNA created by viral replication and gene expression binds to the N-terminal domain, activating the protein. Once active, PKR is able to phosphorylate the eukaryotic translation initiation factor EIF2A. This inhibits further cellular mRNA translation, thereby preventing viral protein synthesis. Since ElF2A is involved in the commonly initiation translation from 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 upregulates the expression of Interferon cytokines, which work to spread the antiviral signal locally. Active PKR is also able to activate tumor suppressor PP2A which regulates the cell cycle and the metabolism. Through complex mechanisms, active PKR is also able to induce cellular apoptosis, 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 stress of endoplasmic reticulum (ER). PKR pathway leads to stress response through activation of other stress pathway such as JNK, p38, NFkB, PP2A and phosphorylation of EIF2A. 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, ElF2A, insulin receptor and others. This metabolically activated inflammatory complex is called metabolic inflammasome or metaflammasome.

Viral defense

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

For instance, Epstein-Barr Virus (EBV) uses the gene EBER-1 to produce decoy dsRNA. This leads to cancers such as Burkitt's lymphoma, Hodgkin's Disease, nasopharyngeal carcinoma and various leukemias.

Viral defence mechanisms against PKR

Defence type	Virus	Molecule
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 block	Influenza 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.

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 with:

• ASK1,
• DNAJC3,
• ILF3,
• METAP2,
• P53,
• PPP1CA,
• PRKRA,
• STAT1, and
• TARBP2.