Protein kinase R

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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 that in humans is encoded by the EIF2AK2 gene.[1][2]

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 eIF2α. This inhibits further cellular mRNA translation, thereby preventing viral protein synthesis. Since ElF2α 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 ER stress. PKR pathway leads to stress response through activation of other stress pathway such as JNK, p38, NFkB, PP2A 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.[3][4]

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.[5]

Fetal alcohol syndrome

PKR also mediates ethanol-induced protein synthesis inhibition and apoptosis which is linked to fetal alcohol syndrome.[6]

Interactions

Protein kinase R has been shown to interact with:

References

  1. ↑ "Entrez Gene: EIF2AK2 eukaryotic translation initiation factor 2-alpha kinase 2".
  2. ↑ Feng GS, Chong K, Kumar A, Williams BR (June 1992). "Identification of double-stranded RNA-binding domains in the interferon-induced double-stranded RNA-activated p68 kinase". Proc. Natl. Acad. Sci. U.S.A. 89 (12): 5447–51. doi:10.1073/pnas.89.12.5447. PMC 49309. PMID 1351683.
  3. ↑ García MA, Gil J, Ventoso I, Guerra S, Domingo E, Rivas C, Esteban M (December 2006). "Impact of protein kinase PKR in cell biology: from antiviral to antiproliferative action". Microbiol. Mol. Biol. Rev. 70 (4): 1032–60. doi:10.1128/MMBR.00027-06. PMC 1698511. PMID 17158706.
  4. ↑ Hotamisligil GS (2010). "Endoplasmic reticulum stress and the inflammatory basis of metabolic disease". Cell. 140 (6): 900–17. doi:10.1016/j.cell.2010.02.034. PMC 2887297. PMID 20303879.
  5. ↑ Zhu PJ, Huang W, Kalikulov D, Yoo JW, Placzek AN, Stoica L, Zhou H, Bell JC, Friedlander MJ, Krnjević K, Noebels JL, Costa-Mattioli M (December 2011). "Suppression of PKR Promotes Network Excitability and Enhanced Cognition by Interferon-γ-Mediated Disinhibition". Cell. 147 (6): 1384–96. doi:10.1016/j.cell.2011.11.029. PMC 3569515. PMID 22153080. Lay summary – canada.com.
  6. ↑ Chen G, Ma C, Bower KA, Ke Z, Luo J (June 2006). "Interaction between RAX and PKR modulates the effect of ethanol on protein synthesis and survival of neurons". J. Biol. Chem. 281 (23): 15909–15. doi:10.1074/jbc.M600612200. PMID 16574643.
  7. ↑ Takizawa T, Tatematsu C, Nakanishi Y (December 2002). "Double-stranded RNA-activated protein kinase interacts with apoptosis signal-regulating kinase 1. Implications for apoptosis signaling pathways". Eur. J. Biochem. 269 (24): 6126–32. doi:10.1046/j.1432-1033.2002.03325.x. PMID 12473108.
  8. ↑ 8.0 8.1 Polyak SJ, Tang N, Wambach M, Barber GN, Katze MG (January 1996). "The P58 cellular inhibitor complexes with the interferon-induced, double-stranded RNA-dependent protein kinase, PKR, to regulate its autophosphorylation and activity". J. Biol. Chem. 271 (3): 1702–7. doi:10.1074/jbc.271.3.1702. PMID 8576172.
  9. ↑ Saunders LR, Perkins DJ, Balachandran S, Michaels R, Ford R, Mayeda A, Barber GN (August 2001). "Characterization of two evolutionarily conserved, alternatively spliced nuclear phosphoproteins, NFAR-1 and -2, that function in mRNA processing and interact with the double-stranded RNA-dependent protein kinase, PKR". J. Biol. Chem. 276 (34): 32300–12. doi:10.1074/jbc.M104207200. PMID 11438536.
  10. ↑ Langland JO, Kao PN, Jacobs BL (May 1999). "Nuclear factor-90 of activated T-cells: A double-stranded RNA-binding protein and substrate for the double-stranded RNA-dependent protein kinase, PKR". Biochemistry. 38 (19): 6361–8. doi:10.1021/bi982410u. PMID 10320367.
  11. ↑ Parker LM, Fierro-Monti I, Mathews MB (August 2001). "Nuclear factor 90 is a substrate and regulator of the eukaryotic initiation factor 2 kinase double-stranded RNA-activated protein kinase". J. Biol. Chem. 276 (35): 32522–30. doi:10.1074/jbc.M104408200. PMID 11438540.
  12. ↑ Patel RC, Vestal DJ, Xu Z, Bandyopadhyay S, Guo W, Erme SM, Williams BR, Sen GC (July 1999). "DRBP76, a double-stranded RNA-binding nuclear protein, is phosphorylated by the interferon-induced protein kinase, PKR". J. Biol. Chem. 274 (29): 20432–7. doi:10.1074/jbc.274.29.20432. PMID 10400669.
  13. ↑ Gil J, Esteban M, Roth D (December 2000). "In vivo regulation of the dsRNA-dependent protein kinase PKR by the cellular glycoprotein p67". Biochemistry. 39 (51): 16016–25. doi:10.1021/bi001754t. PMID 11123929.
  14. ↑ Cuddihy AR, Wong AH, Tam NW, Li S, Koromilas AE (April 1999). "The double-stranded RNA activated protein kinase PKR physically associates with the tumor suppressor p53 protein and phosphorylates human p53 on serine 392 in vitro". Oncogene. 18 (17): 2690–702. doi:10.1038/sj.onc.1202620. PMID 10348343.
  15. ↑ Tan SL, Tareen SU, Melville MW, Blakely CM, Katze MG (September 2002). "The direct binding of the catalytic subunit of protein phosphatase 1 to the PKR protein kinase is necessary but not sufficient for inactivation and disruption of enzyme dimer formation". J. Biol. Chem. 277 (39): 36109–17. doi:10.1074/jbc.M205109200. PMID 12138106.
  16. ↑ Huang X, Hutchins B, Patel RC (August 2002). "The C-terminal, third conserved motif of the protein activator PACT plays an essential role in the activation of double-stranded-RNA-dependent protein kinase (PKR)". Biochem. J. 366 (Pt 1): 175–86. doi:10.1042/BJ20020204. PMC 1222748. PMID 11985496.
  17. ↑ Patel RC, Sen GC (August 1998). "PACT, a protein activator of the interferon-induced protein kinase, PKR". EMBO J. 17 (15): 4379–90. doi:10.1093/emboj/17.15.4379. PMC 1170771. PMID 9687506.
  18. ↑ Wong AH, Tam NW, Yang YL, Cuddihy AR, Li S, Kirchhoff S, Hauser H, Decker T, Koromilas AE (March 1997). "Physical association between STAT1 and the interferon-inducible protein kinase PKR and implications for interferon and double-stranded RNA signaling pathways". EMBO J. 16 (6): 1291–304. doi:10.1093/emboj/16.6.1291. PMC 1169727. PMID 9135145.
  19. ↑ Wong AH, Durbin JE, Li S, Dever TE, Decker T, Koromilas AE (April 2001). "Enhanced antiviral and antiproliferative properties of a STAT1 mutant unable to interact with the protein kinase PKR". J. Biol. Chem. 276 (17): 13727–37. doi:10.1074/jbc.M011240200. PMID 11278865.
  20. ↑ Cosentino GP, Venkatesan S, Serluca FC, Green SR, Mathews MB, Sonenberg N (October 1995). "Double-stranded-RNA-dependent protein kinase and TAR RNA-binding protein form homo- and heterodimers in vivo". Proc. Natl. Acad. Sci. U.S.A. 92 (21): 9445–9. doi:10.1073/pnas.92.21.9445. PMC 40818. PMID 7568151.
  21. ↑ Daher A, Longuet M, Dorin D, Bois F, Segeral E, Bannwarth S, Battisti PL, Purcell DF, Benarous R, Vaquero C, Meurs EF, Gatignol A (September 2001). "Two dimerization domains in the trans-activation response RNA-binding protein (TRBP) individually reverse the protein kinase R inhibition of HIV-1 long terminal repeat expression". J. Biol. Chem. 276 (36): 33899–905. doi:10.1074/jbc.M103584200. PMID 11438532.

Further reading

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