Protein kinase R

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.^[1][2]

PKR protects against viral infections.

Mechanism of action

PKR is activated by double-stranded RNA (dsRNA), the synthesis of which is caused virally. 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 translation initiation factor EIF2A. 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, 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 (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.

Memory and learning

PKR knockout mice or inhibition of PKR in mice enhances memory and learning.^[3]

Fetal alcohol syndrome

PKR also mediates ethanol-induced protein synthesis inhibition and apoptosis which is linked to fetal alcohol syndrome.^[4]

Interactions

Protein kinase R has been shown to interact with:

• ASK1,^[5]
• DNAJC3,^[6][6]
• ILF3,^{[7][8][9][10]}
• METAP2,^[11]
• P53,^[12]
• PPP1CA,^[13]
• PRKRA,^[14][15]
• STAT1,^[16][17] and
• TARBP2.^[18][19]

References

Further reading