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

Enzyme

Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

 that in humans is encoded by the EIF2AK2 gene

Gene

A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...

.

PKR protects against viral infections.

Mechanism

PKR is activated by double-stranded RNA (dsRNA), the synthesis of which is caused virally. PKR can also be activated by the protein PACT

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 is a protein that in humans is encoded by the PRKRA gene...

 or by heparin. PKR contains an N-terminal dsRNA binding domain (dsRBD) and a C-terminal kinase

Kinase

In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...

 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

Interferon

Interferons are proteins made and released by host cells in response to the presence of pathogens—such as viruses, bacteria, or parasites—or tumor cells. They allow communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.IFNs belong to...

 in a latent state. Binding to dsRNA is believed to activate PKR by inducing dimerization and subsequent auto-phosphorylation

Phosphorylation

Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....

 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 translation initiation factor EIF2A

EIF2A

Eukaryotic translation initiation factor 2A is a protein that in humans is encoded by the EIF2A gene.-Further reading:...

. This inhibits further cellular mRNA translation, thereby preventing viral protein synthesis. 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. Through complex mechanisms, active PKR is also able to induce cellular apoptosis

Apoptosis

Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

, to prevent further viral spread.

Viral defense

Viruses have developed many mechanisms to outfox 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

Epstein-Barr virus

The Epstein–Barr virus , also called human herpesvirus 4 , is a virus of the herpes family and is one of the most common viruses in humans. It is best known as the cause of infectious mononucleosis...

 (EBV) uses the gene EBER-1 to produce decoy dsRNA. This leads to cancers such as Burkitt's lymphoma

Burkitt's lymphoma

Burkitt's lymphoma is a cancer of the lymphatic system...

, Hodgkin's Disease, nasopharyngeal carcinoma

Nasopharyngeal carcinoma

Nasopharyngeal carcinoma is the most common cancer originating in the nasopharynx, the uppermost region of the pharynx , behind the nose where the nasal passages and auditory tubes join the remainder of the upper respiratory tract. NPC differs significantly from other cancers of the head and neck...

 and various leukemias.

Viral defence mechanisms against PKR

Defence type	Virus	Molecule
Decoy dsRNA	Adenovirus	VAI RNA
	Epstein-Barr virus Epstein-Barr virus The Epstein–Barr virus , also called human herpesvirus 4 , is a virus of the herpes family and is one of the most common viruses in humans. It is best known as the cause of infectious mononucleosis...	EBER EBER EBER refers to two short small nuclear RNAs associated with the Epstein-Barr virus.EBER1 and EBER2 are 167 and 172 nucleotides in length respectively. They are not required for EBV-mediated growth transformation. These two RNAs are transcribed by the host's RNA polymerase III even during a latent...
	HIV HIV Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...	TAR Tar Tar is modified pitch produced primarily from the wood and roots of pine by destructive distillation under pyrolysis. Production and trade in tar was a major contributor in the economies of Northern Europe and Colonial America. Its main use was in preserving wooden vessels against rot. The largest...
PKR degradation	Poliovirus Poliovirus Poliovirus, the causative agent of poliomyelitis, is a human enterovirus and member of the family of Picornaviridae.Poliovirus is composed of an RNA genome and a protein capsid. The genome is a single-stranded positive-sense RNA genome that is about 7500 nucleotides long. The viral particle is...	2Apro
hide viral dsRNA	Vaccinia virus	E3L
	Reovirus	σ3
	Influenza virus	NS1
Dimerization block	Influenza virus	p58IPK
	Hepatitis C virus Hepatitis C virus Hepatitis C virus is a small , enveloped, positive-sense single-stranded RNA virus of the family Flaviviridae...	NS5A
Pseudosubstrate	Vaccinia virus	K3L
	HIV	Tat
Dephosphorylation of substrate	Herpes simplex virus Herpes simplex virus Herpes simplex virus 1 and 2 , also known as Human herpes virus 1 and 2 , are two members of the herpes virus family, Herpesviridae, that infect humans. Both HSV-1 and HSV-2 are ubiquitous and contagious...	ICP34.5

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

Protein-protein interaction

Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...

 with ASK1

ASK1

Apoptosis signal-regulating kinase 1 also known as mitogen-activated protein kinase kinase kinase 5 is a member of MAP kinase kinase kinase family and as such a part of mitogen-activated protein kinase pathway...

, PPP1CA

PPP1CA

Serine/threonine-protein phosphatase PP1-alpha catalytic subunit is an enzyme that in humans is encoded by the PPP1CA gene.-Interactions:...

, STAT1

STAT1

STAT1 is a member of the Signal Transducers and Activators of Transcription family of transcription factors. STAT1 is involved in upregulating genes due to a signal by either type I, type II or type III interferons...

, ILF3

ILF3

Interleukin enhancer-binding factor 3 is a protein that in humans is encoded by the ILF3 gene.-Interactions:ILF3 has been shown to interact with XPO5, FUS, Protein kinase R, PRMT1 and DNA-PKcs....

, DNAJC3

DNAJC3

DnaJ homolog subfamily C member 3 is a protein that in humans is encoded by the DNAJC3 gene.-Interactions:DNAJC3 has been shown to interact with Protein kinase R, PRKRIR and EIF2AK3.-Further reading:...

, P53

P53

p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...

, TARBP2

TARBP2

RISC-loading complex subunit TARBP2 is a protein that in humans is encoded by the TARBP2 gene.-Interactions:TARBP2 has been shown to interact with Protein kinase R and RBM14.-Further reading:...

, METAP2

METAP2

Methionine aminopeptidase 2 is an enzyme that in humans is encoded by the METAP2 gene.- Function :This gene is a member of the methionyl aminopeptidase family and encodes a protein that binds 2 cobalt or manganese ions...

 and PRKRA

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 is a protein that in humans is encoded by the PRKRA gene...

.

Further reading